Neuroactive steroids and methods of use thereof

ABSTRACT

(3alpha,3beta)-disubstituted 17beta steroidal compounds, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, are provided for the prevention and treatment of a variety of CNS-related conditions.

RELATED APPLICATIONS

The present application claim priority under 35 U.S.C. §119(e) to U.S.provisional patent application U.S. Ser. No. 61/779,735, filed Mar. 13,2013, which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Brain excitability is defined as the level of arousal of an animal, acontinuum that ranges from coma to convulsions, and is regulated byvarious neurotransmitters. In general, neurotransmitters are responsiblefor regulating the conductance of ions across neuronal membranes. Atrest, the neuronal membrane possesses a potential (or membrane voltage)of approximately −70 mV, the cell interior being negative with respectto the cell exterior. The potential (voltage) is the result of ion (K+,Na+, Cl−, organic anions) balance across the neuronal semipermeablemembrane. Neurotransmitters are stored in presynaptic vesicles and arereleased as a result of neuronal action potentials. When released intothe synaptic cleft, an excitatory chemical transmitter such asacetylcholine will cause membrane depolarization (change of potentialfrom −70 mV to −50 mV). This effect is mediated by postsynapticnicotinic receptors which are stimulated by acetylcholine to increasethe membrane permeability of Na+ ions. The reduced membrane potentialincreases the probability of generating a postsynaptic action potential,which amounts to an increase in neuronal excitability.

NMDA receptors are highly expressed in the CNS and are involved inexcitatory synaptic transmission. Activating these receptors contributesto synaptic plasticity in some circumstances and excitotoxicity inothers. These receptors are ligand-gated ion channels that admit Ca2+after binding of the neurotransmitters glutamate and glycine, and arefundamental to excitatory neurotransmission and normal CNS function.NMDA receptors are heteromeric complexes comprised of NR1, NR2, and/orNR3 subunits and possess distinct recognition sites for exogenous andendogenous ligands. These recognition sites include binding sites forglycine, and glutamate agonists and modulators. Positive modulators maybe useful as therapeutic agents with potential clinical uses ascognitive enhancers and in the treatment of psychiatric disorders inwhich glutamatergic transmission is reduced or defective (see, e.g.,Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). Incontrast, negative modulators may be useful as therapeutic agenst withpotential clinical uses in the treatment of psychiatric disorders inwhich glutamatergic transmission is pathologically increased (e.g.,treatment resistant depression).

Neuroactive steroids such as pregnenolone sulfate (PS) have been shownto exert direct modulatory effects on several types of neurotransmitterreceptors, such as GABAA, glycine, AMPA, kainate, and NMDA receptors.NMDA receptors are positively modulated by PS; however, the degree ofmodulation varies considerably, e.g., depending upon the subunitcomposition of the receptor.

In addition to PS, several other 3β-hydroxy steroids have been shown topotentiate NMDA receptors (see, e.g., Paul et al., J. Pharm. and Exp.Ther. 1994, 271, 677-682). Recently, a 3β-hydroxy-ergost-5-ene steroidderivative, referred to as Org-1, was reported as positive modulator ofNMDA (NR1a/NR2A). Org-1 was found to selectively modulate NMDA overGABAA (see, e.g., Madau et al., Program No. 613.2/B87. 2009 NeuroscienceMeeting Planner. Chicago, Ill.: Society for Neuroscience, 2009; Connicket al., Program No. 613.1/B86. 2009 Neuroscience Meeting Planner.Chicago, Ill.: Society for Neuroscience, 2009; Paul el al., J. Neurosci.2013, 33, 17290-17300).

New and improved neuroactive steroids are needed that modulate brainexcitability for the prevention and treatment of CNS-related conditions.The compounds, compositions, and methods described herein are directedtoward this end.

SUMMARY OF THE INVENTION

The inventors of the present invention, during an on-going explorationof Org-1 analogs for NMDA modulation, a portion of which is described inPCT/US2012/054261, incorporated herein by reference, discovered severalspecific combination of elements which provides NMDA modulators withcomparatively superior properties. For example, as shown in Table 1,compounds bearing a beta-hydrogen at C₅ are disfavored compared tocompounds bearing either alpha-hydrogen C₅ or double bond across C₅-C₆due to loss of potentiation of the NMDA receptor. The removal of themethyl at C₂₁ also results in significant loss of NMDA potentiation.Disubstitution at C₃ is expected to increase metabolic stability ofthese compounds and is thus a preferrred feature of the invention.Fluorination on the C₁₇ side chain has been shown to improve potency andlimit maximum potentiation of the NMDA receptor when tested as high as 1μM concentration of compound. A secondary or tertiary terminal alcoholon the C₁₇ side chain has been shown to improve potency and limitmaximum potentiation of the NMDA receptor when tested as high as 1 μMconcentration of compound, and is thus a preferred feature of theinvention, with a preference for bulkier groups at the terminating endcontaining 2-3 carbons, or a group comprising fluorine substitution.Such properties are expected limit the risk of inducing glutamate drivenneurotoxicity relative to compounds that achieve a greater maximumpotentiation of the NMDA receptor. Compounds of the present inventionencompass various combinations of these specified features to providesuperior NMDA modulators.

Thus, in one aspect, provided are compounds of Formula (I),

and pharmaceutically acceptable salts thereof;wherein:

R¹ is substituted or unsubstituted aliphatic;

R² is hydrogen, halogen, substituted or unsubstituted C₁₋₆alkyl,substituted or unsubstituted cyclopropyl, or —OR^(A2), wherein R^(A2) ishydrogen or substituted or unsubstituted alkyl;

R^(3a) is hydrogen or —OR^(A3), wherein R^(A3) is hydrogen orsubstituted or unsubstituted alkyl, and R^(3b) is hydrogen; or R^(3a)and R^(3b) are joined to form an oxo (═O) group;

R⁴ is hydrogen, substituted or unsubstituted alkyl, or halogen;

X is —C(R^(X))₂— or —O—, wherein R^(X) is hydrogen or fluorine, or oneR^(X) group and R^(5b) are joined to form a double bond;

each instance of R^(5a) and R^(5b) is independently hydrogen orfluorine;

R^(6a) is a non-hydrogen group selected from the group consisting ofsubstituted and unsubstituted alkyl, substituted and unsubstitutedalkenyl, substituted and unsubstituted alkynyl, substituted andunsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl,substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl group, wherein the non-hydrogen group is optionallysubstituted with fluorine; and

R^(6b) is hydrogen or a substituted or unsubstituted alkyl groupoptionally substituted with fluorine;

represents a single or double bond, provided if a single bond ispresent, then the hydrogen at C5 is in the alpha configuration;

and further provided that:

(1) at least one of R^(X), R^(5a), and R^(5b) is fluorine; or

(2) at least one of R^(6a) and R^(6b) is a non-hydrogen groupsubstituted with a fluorine; or

(3) R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms.

In another aspect, provided are pharmaceutical compositions comprising acompound of Formula (I), or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable excipient.

In yet another aspect, provided is a method for treating or preventing aCNS-related condition associated with NMDA modulation comprisingadministering to a subject in need thereof an effective amount of acompound or pharmaceutically acceptable salt thereof, or pharmaceuticalcomposition thereof. In certain embodiments, the CNS-related conditionis an adjustment disorder, anxiety disorder (includingobsessive-compulsive disorder, posttraumatic stress disorder, socialphobia, and generalized anxiety disorder), cognitive disorder (includingAlzheimer's disease and other forms of dementia), dissociative disorder,eating disorder, mood disorder (including depression, bipolar disorder,and dysthymic disorder), schizophrenia or other psychotic disorder(including schizoaffective disorder), sleep disorder (includinginsomnia), substance abuse-related disorder, personality disorder(including obsessive-compulsive personality disorder), autism spectrumdisorders (including those involving mutations to the Shank group ofproteins), neurodevelopmental disorder (including Rett syndrome), pain(including acute and chronic pain), seizure disorder (including statusepilepticus and monogenic forms of epilepsy such as Dravet's disease,and Tuberous Sclerosis complex (TSC)), stroke, traumatic brain injury,movement disorder (including Huntington's disease and Parkinson'sdisease) and tinnitus. In certain embodiments, these compounds can beused to induce sedation or anesthesia.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

DEFINITIONS Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

“Aliphatic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group,as defined herein.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group having from 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 12 carbon atoms (“C₁₋₁₂alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms(“C₁₋₁₀ alkyl”). In some embodiments, an alkyl group has 1 to 9 carbonatoms (“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8carbon atoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1to 7 carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl grouphas 1 to 6 carbon atoms (“C₁₋₆ alkyl”, also referred to herein as “loweralkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms(“C₁₋₅ alkyl”). In some embodiments, an alkyl group has 1 to 4 carbonatoms (“C₁₋₄ alkyl”). In some embodiments, an alkyl group has 1 to 3carbon atoms (“C₁₋₃ alkyl”). In some embodiments, an alkyl group has 1to 2 carbon atoms (“C₁₋₂ alkyl”). In some embodiments, an alkyl grouphas 1 carbon atom (“C₁ alkyl”). In some embodiments, an alkyl group has2 to 6 carbon atoms (“C₂₋₆ alkyl”). Examples of C₁₋₆ alkyl groupsinclude methyl (C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl(C₄), tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), and n-hexyl (C₆). Additional examples of alkylgroups include n-heptyl (C₇), n-octyl (C₈) and the like. Unlessotherwise specified, each instance of an alkyl group is independentlyoptionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents;e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1substituent. In certain embodiments, the alkyl group is unsubstitutedC₁₋₁₀ alkyl (e.g., —CH₃). In certain embodiments, the alkyl group issubstituted C₁₋₁₀ alkyl. Common alkyl abbreviations include Me (—CH₃),Et (—CH₂CH₃), iPr (—CH(CHh)₂), nPr (—CH₂CH₂CH₃), n-Bu (—CH₂CH₂CH₂CH₃),or i-Bu (—CH₂CH(CH₃)₂).

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group, respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” and “alkynylene” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and “alkynylene”groups may be substituted or unsubstituted with one or more substituentsas described herein.

“Alkylene” refers to an alkyl group wherein two hydrogens are removed toprovide a divalent radical, and which may be substituted orunsubstituted. Unsubstituted alkylene groups include, but are notlimited to, methylene (—CH₂—), ethylene (—CH₂CH₂—), propylene(—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—), pentylene (—CH₂CH₂CH₂CH₂CH₂—),hexylene (—CH₂CH₂CH₂CH₂CH₂CH₂—), and the like. Exemplary substitutedalkylene groups, e.g., substituted with one or more alkyl (methyl)groups, include but are not limited to, substituted methylene(—CH(CH₃)—, (—C(CH₃)₂—), substituted ethylene (—CH(CH₃)CH₂—,—CH₂CH(CH₃)—, —C(CH₃)₂CH₂—, —CH₂C(CH₃)₂—), substituted propylene(—CH(CH₃)CH₂CH₂—, —CH₂CH(CH₃)CH₂—, —CH₂CH₂CH(CH₃)—, —C(CH₃)₂CH₂CH₂—,—CH₂C(CH₃)₂CH₂—, —CH₂CH₂C(CH₃)₂—), and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkenyl group is independently optionally substituted,i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a“substituted alkenyl”) with one or more substituents e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkenyl group is unsubstituted C₂₋₁₀ alkenyl.In certain embodiments, the alkenyl group is substituted C₂₋₁₀ alkenyl.

“Alkenylene” refers to an alkenyl group wherein two hydrogens areremoved to provide a divalent radical, and which may be substituted orunsubstituted. Exemplary unsubstituted divalent alkenylene groupsinclude, but are not limited to, ethenylene (—CH═CH—) and propenylene(e.g., —CH═CHCH₂—, —CH₂—CH═CH—). Exemplary substituted alkenylenegroups, e.g., substituted with one or more alkyl (methyl) groups,include but are not limited to, substituted ethylene (—C(CH₃)═CH—,—CH═C(CH₃)—), substituted propylene (e.g., —C(CH₃)═CHCH₂—,—CH═C(CH₃)CH₂—, —CH═CHCH(CH₃)—, —CH═CHC(CH₃)₂—, —CH(CH₃)—CH═CH—,—C(CH₃)₂—CH═CH—, —CH₂—C(CH₃)═CH—, —CH₂—CH═C(CH₃)—), and the like.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like. Unless otherwise specified, each instance of analkynyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted alkynyl”) or substituted (a“substituted alkynyl”) with one or more substituents; e.g., for instancefrom 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Incertain embodiments, the alkynyl group is unsubstituted C₂₋₁₀ alkynyl.In certain embodiments, the alkynyl group is substituted C₂₋₁₀ alkynyl.

“Alkynylene” refers to a linear alkynyl group wherein two hydrogens areremoved to provide a divalent radical, and which may be substituted orunsubstituted. Exemplary divalent alkynylene groups include, but are notlimited to, substituted or unsubstituted ethynylene, substituted orunsubstituted propynylene, and the like.

The term “heteroalkyl,” as used herein, refers to an alkyl group, asdefined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4)heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus)within the parent chain, wherein the one or more heteroatoms is insertedbetween adjacent carbon atoms within the parent carbon chain and/or oneor more heteroatoms is inserted between a carbon atom and the parentmolecule, i.e., between the point of attachment. In certain embodiments,a heteroalkyl group refers to a saturated group having from 1 to 10carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₁₀ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₉ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 8carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₈ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 7carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC₁₋₇ alkyl”). In someembodiments, a heteroalkyl group is a group having 1 to 6 carbon atomsand 1, 2, or 3 heteroatoms (“heteroC₁₋₆ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms (“heteroC₁₋₄ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1heteroatom (“heteroC₁₋₃ alkyl”). In some embodiments, a heteroalkylgroup is a saturated group having 1 to 2 carbon atoms and 1 heteroatom(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC₂₋₆ alkyl”).Unless otherwise specified, each instance of a heteroalkyl group isindependently unsubstituted (an “unsubstituted heteroalkyl”) orsubstituted (a “substituted heteroalkyl”) with one or more substituents.In certain embodiments, the heteroalkyl group is an unsubstitutedheteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkyl group is asubstituted heteroC₁₋₁₀ alkyl.

The term “heteroalkenyl,” as used herein, refers to an alkenyl group, asdefined herein, which further comprises one or more (e.g., 1, 2, 3, or4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus) wherein the one or more heteroatoms is inserted betweenadjacent carbon atoms within the parent carbon chain and/or one or moreheteroatoms is inserted between a carbon atom and the parent molecule,i.e., between the point of attachment. In certain embodiments, aheteroalkenyl group refers to a group having from 2 to 10 carbon atoms,at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC₂₋₁₀alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbonatoms at least one double bond, and 1, 2, 3, or 4 heteroatoms(“heteroC₂₋₉ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4heteroatoms (“heteroC₂₋₈ alkenyl”). In some embodiments, a heteroalkenylgroup has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or4 heteroatoms (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1, 2, or 3 heteroatoms (“heteroC₂₋₆ alkenyl”). In some embodiments,a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₄ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 3 carbon atoms, at least one double bond,and 1 heteroatom (“heteroC₂₋₃ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or 2 heteroatoms (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “heteroalkynyl,” as used herein, refers to an alkynyl group, asdefined herein, which further comprises one or more (e.g., 1, 2, 3, or4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon,phosphorus) wherein the one or more heteroatoms is inserted betweenadjacent carbon atoms within the parent carbon chain and/or one or moreheteroatoms is inserted between a carbon atom and the parent molecule,i.e., between the point of attachment. In certain embodiments, aheteroalkynyl group refers to a group having from 2 to 10 carbon atoms,at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroC₂₋₁₀alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbonatoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms(“heteroC₂₋₉ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4heteroatoms (“heteroC₂₋₈ alkynyl”). In some embodiments, a heteroalkynylgroup has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or4 heteroatoms (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1, 2, or 3 heteroatoms (“heteroC₂₋₆ alkynyl”). In some embodiments,a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₄ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond,and 1 heteroatom (“heteroC₂₋₃ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

As used herein, “alkylene,” “alkenylene,” “alkynylene,”“heteroalkylene,” “heteroalkenylene,” and “heteroalkynylene,” refer to adivalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl,heteroalkenyl, and heteroalkynyl group respectively. When a range ornumber of carbons is provided for a particular “alkylene,” “alkenylene,”“alkynylene,” “heteroalkylene,” “heteroalkenylene,” or“heteroalkynylene,” group, it is understood that the range or numberrefers to the range or number of carbons in the linear carbon divalentchain. “Alkylene,” “alkenylene,” “alkynylene,” “heteroalkylene,”“heteroalkenylene,” and “heteroalkynylene” groups may be substituted orunsubstituted with one or more substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl. Unless otherwise specified, eachinstance of an aryl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted aryl”) or substituted (a “substitutedaryl”) with one or more substituents. In certain embodiments, the arylgroup is unsubstituted C₆₋₁₄ aryl. In certain embodiments, the arylgroup is substituted C₆₋₁₄ aryl.

In certain embodiments, an aryl group substituted with one or more ofgroups selected from halo, C₁-C₈ alkyl, C₁-C₈ haloalkyl, cyano, hydroxy,C₁-C₈ alkoxy, and amino.

Examples of representative substituted aryls include the following

wherein one of R⁵⁶ and R⁵⁷ may be hydrogen and at least one of R⁵⁶ andR⁵⁷ is each independently selected from C₁-C₈ alkyl, C₁-C₈ haloalkyl,4-10 membered heterocyclyl, alkanoyl, C₁-C₈ alkoxy, heteroaryloxy,alkylamino, arylamino, heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹NR⁵⁸SO₂R⁵⁹,COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, SO₂NR⁵⁸R⁵⁹, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵⁶ and R⁵⁷ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O, or S. R⁶⁰ and R⁶¹ are independently hydrogen, C₁-C₈ alkyl, C₁-C₄haloalkyl, C₃-C₁₀cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,substituted C₆-C₁₀ aryl, 5-10 membered heteroaryl, or substituted 5-10membered heteroaryl.

Other representative aryl groups having a fused heterocyclyl groupinclude the following:

wherein each W is selected from C(R⁶⁶)₂, NR⁶⁶, O, and S; and each Y isselected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independentlyhydrogen, C₁-C₈ alkyl, C₃-C₁₀cycloalkyl, 4-10 membered heterocyclyl,C₆-C₁₀aryl, and 5-10 membered heteroaryl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Aralkyl” is a subset of alkyl and aryl, as defined herein, and refersto an optionally substituted alkyl group substituted by an optionallysubstituted aryl group.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently optionally substituted, i.e., unsubstituted (an“unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”)with one or more substituents. In certain embodiments, the heteroarylgroup is unsubstituted 5-14 membered heteroaryl. In certain embodiments,the heteroaryl group is substituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyL and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀aryl, and 5-10 membered heteroaryl.

“Heteroaralkyl” is a subset of alkyl and heteroaryl, as defined herein,and refers to an optionally substituted alkyl group substituted by anoptionally substituted heteroaryl group.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₈₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₁₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system. Unless otherwise specified, each instance of acarbocyclyl group is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is unsubstituted C₃₋₁₀ carbocyclyl.In certain embodiments, the carbocyclyl group is a substituted C₃₋₁₀carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 10 ring carbon atoms (“C₁₋₁₀cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ringcarbon atoms (“C₃₋₈ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 6 ring carbon atoms (“C₃₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C₅₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ cycloalkyl”). Examples of C₅₋₆ cycloalkyl groupsinclude cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C₃₋₆cycloalkyl groups include the aforementioned C₅₋₆ cycloalkyl groups aswell as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C₃₋₈cycloalkyl groups include the aforementioned C₃₋₆ cycloalkyl groups aswell as cycloheptyl (C₇) and cyclooctyl (C₈). Unless otherwisespecified, each instance of a cycloalkyl group is independentlyunsubstituted (an “unsubstituted cycloalkyl”) or substituted (a“substituted cycloalkyl”) with one or more substituents. In certainembodiments, the cycloalkyl group is unsubstituted C₁₋₁₀ cycloalkyl. Incertain embodiments, the cycloalkyl group is substituted C₃₋₁₀cycloalkyl.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently optionally substituted, i.e.,unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a“substituted heterocyclyl”) with one or more substituents. In certainembodiments, the heterocyclyl group is unsubstituted 3-10 memberedheterocyclyl. In certain embodiments, the heterocyclyl group issubstituted 3-10 membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Particular examples of heterocyclyl groups are shown in the followingillustrative examples:

wherein each W is selected from CR⁶⁷, C(R⁶⁷)₂, NR⁶⁷, O, and S; and eachY is selected from NR⁶⁷, O, and S; and R⁶⁷ is independently hydrogen,C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,5-10 membered heteroaryl. These heterocyclyl rings may be optionallysubstituted with one or more groups selected from the group consistingof acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoylor amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl,aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto,nitro, thiol, —S-alkyl, —S-aryl, —S(O)-alkyl, —S(O)-aryl, —S(O)₂-alkyl,and —S(O)₂-aryl. Substituting groups include carbonyl or thiocarbonylwhich provide, for example, lactam and urea derivatives.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcarbocyclyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl, asdefined herein. “Alkanoyl” is an acyl group wherein R²⁰ is a group otherthan hydrogen. Representative acyl groups include, but are not limitedto, formyl (—CHO), acetyl (—C(═O)CH₃), cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl (—C(═O)Ph), benzylcarbonyl(—C(═O)CH₂Ph), —C(O)—C₁-C₈ alkyl, —C(O)—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)—(CH₂)_(t)(5-10 membered heteroaryl),—C(O)—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4. In certainembodiments, R²¹ is C₁-C₈ alkyl, substituted with halo or hydroxy; orC₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀aryl, arylalkyl,5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy.

“Acylamino” refers to a radical —NR²²C(O)R²³, where each instance of R²²and R23 is independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted carbocyclyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl, as defined herein, or R²² is anamino protecting group. Exemplary “acylamino” groups include, but arenot limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonylamino.Particular exemplary “acylamino” groups are —NR²⁴C(O)—C₁-C₈ alkyl,—NR²⁴C(O)—(CH₂)_(t)(C₆—C o aryl), —NR²⁴C(O)—(CH₂)_(t)(5-10 memberedheteroaryl), —NR²⁴C(O)—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR²⁴C(O)—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, and each R²⁴ independently represents H or C₁-C₈ alkyl. Incertain embodiments, R²⁵ is H, C₁-C₈ alkyl, substituted with halo orhydroxy; C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; and R²⁶ is H, C₁-C₈ alkyl,substituted with halo or hydroxy; C₃-C₁₀cycloalkyl, 4-10 memberedheterocyclyl, C₆-C₁₀aryl, arylalkyl, 5-10 membered heteroaryl orheteroarylalkyl, each of which is substituted with unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxyl; provided at least one of R²⁵ and R²⁶ is other than H.

“Acyloxy” refers to a radical —OC(O)R²⁷, where R²⁷ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl, as defined herein. Representative examples include, but arenot limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. In certainembodiments, R²⁸ is C₁-C₈ alkyl, substituted with halo or hydroxy;C₃-C₁₀cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀aryl, arylalkyl,5-10 membered heteroaryl or heteroarylalkyl, each of which issubstituted with unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy.

“Alkoxy” refers to the group —OR²⁹ where R²⁹ is substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, or substituted or unsubstituted heteroaryl. Particular alkoxygroups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6carbon atoms. Further particular alkoxy groups have between 1 and 4carbon atoms.

In certain embodiments, R²⁹ is a group that has 1 or more substituents,for instance from 1 to 5 substituents, and particularly from 1 to 3substituents, in particular 1 substituent, selected from the groupconsisting of amino, substituted amino, C₆-C₁₀ aryl, aryloxy, carboxyl,cyano, C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Exemplary‘substituted alkoxy’ groups include, but are not limited to,—O—(CH₂)_(t)(C₆-C₁₀ aryl), —O—(CH₂)_(t)(5-10 membered heteroaryl),—O—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and —O—(CH₂)_(t)(4-10 memberedheterocyclyl), wherein t is an integer from 0 to 4 and any aryl,heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves besubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. Particular exemplary‘substituted alkoxy’ groups are —OCF₃, —OCH₂CF₃, —OCH₂Ph,—OCH₂-cyclopropyl, —OCH₂CH₂OH, and —OCH₂CH₂NMe₂.

“Amino” refers to the radical —NH₂.

“Substituted amino” refers to an amino group of the formula —N(R³⁸)₂wherein R³⁸ is hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted carbocyclyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or an amino protecting group, wherein at leastone of R³⁸ is not a hydrogen. In certain embodiments, each R³⁸ isindependently selected from hydrogen, C₁-C₈ alkyl, C₃-C₈ alkenyl, C₃-C₈alkynyl, C₆-C₁₀aryl, 5-10 membered heteroaryl, 4-10 memberedheterocyclyl, or C₃-C₁₀ cycloalkyl; or C₁-C₈ alkyl, substituted withhalo or hydroxy; C₃-C₈ alkenyl, substituted with halo or hydroxy; C₃-C₈alkynyl, substituted with halo or hydroxy, or —(CH₂)_(t)(C₆-C₁₀ aryl),—(CH₂)_(t)(5-10 membered heteroaryl), —(CH₂)_(t)(C₃-C₁₀ cycloalkyl), or—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integer between0 and 8, each of which is substituted by unsubstituted C₁-C₄ alkyl,halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy; or both R³⁸ groups are joined to form an alkylene group.

Exemplary “substituted amino” groups include, but are not limited to,—NR³⁹—C₁-C₈ alkyl, —NR³⁹—(CH₂)_(t)(C₆-C₁₀ aryl), —NR³⁹—(CH₂)_(t)(5-10membered heteroaryl), —NR³⁹—(CH₂)_(t)(C₃-C₁₀ cycloalkyl), and—NR³⁹—(CH₂)_(t)(4-10 membered heterocyclyl), wherein t is an integerfrom 0 to 4, for instance 1 or 2, each R³⁹ independently represents H orC₁-C₈ alkyl; and any alkyl groups present, may themselves be substitutedby halo, substituted or unsubstituted amino, or hydroxy; and any aryl,heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselvesbe substituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy. For the avoidance of doubtthe term ‘substituted amino’ includes the groups alkylamino, substitutedalkylamino, alkylarylamino, substituted alkylarylamino, arylamino,substituted arylamino, dialkylamino, and substituted dialkylamino asdefined below.

Substituted amino encompasses both monosubstituted amino anddisubstituted amino groups.

“Azido” refers to the radical —N₃.

“Carbamoyl” or “amido” refers to the radical —C(O)NH₂.

“Substituted carbamoyl” or “substituted amido” refers to the radical—C(O)N(R⁶²)₂ wherein each R⁶² is independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, or an amino protectinggroup, wherein at least one of R⁶² is not a hydrogen. In certainembodiments, R⁶² is selected from H, C₁-C₈ alkyl, C₃-C₁₀ cycloalkyl,4-10 membered heterocyclyl, C₆-C₁₀ aryl, aralkyl, 5-10 memberedheteroaryl, and heteroaralkyl; or C₁-C₈ alkyl substituted with halo orhydroxy; or C₃-C₁₀ cycloalkyl, 4-10 membered heterocyclyl, C₆-C₁₀ aryl,aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which issubstituted by unsubstituted C₁-C₄ alkyl, halo, unsubstituted C₁-C₄alkoxy, unsubstituted C₁-C₄ haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl,or unsubstituted C₁-C₄ haloalkoxy or hydroxy; provided that at least oneR⁶² is other than H.

Exemplary “substituted carbamoyl” groups include, but are not limitedto, —C(O) NR⁶⁴—C₁-C₈ alkyl, —C(O)NR⁶⁴—(CH₂)_(t)(C₆-C₁₀ aryl),—C(O)N⁶⁴—(CH₂)_(t)(5-10 membered heteroaryl), —C(O)NR⁶⁴—(CH₂)_(t)(C₃-C₁₀cycloalkyl), and —C(O)NR⁶⁴—(CH₂)_(t)(4-10 membered heterocyclyl),wherein t is an integer from 0 to 4, each R⁶⁴ independently represents Hor C₁-C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclylgroups present, may themselves be substituted by unsubstituted C₁-C₄alkyl, halo, unsubstituted C₁-C₄ alkoxy, unsubstituted C₁-C₄ haloalkyl,unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted C₁-C₄ haloalkoxy orhydroxy.

“Carboxy” refers to the radical —C(O)OH.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group issubstituted with a cycloalkyl group. Typical cycloalkylalkyl groupsinclude, but are not limited to, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl,cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl,cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

“Heterocyclylalkyl” refers to an alkyl radical in which the alkyl groupis substituted with a heterocyclyl group. Typical heterocyclylalkylgroups include, but are not limited to, pyrrolidinylmethyl,piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl,and the like.

“Cycloalkenyl” refers to substituted or unsubstituted carbocyclyl grouphaving from 3 to 10 carbon atoms and having a single cyclic ring ormultiple condensed rings, including fused and bridged ring systems andhaving at least one and particularly from 1 to 2 sites of olefinicunsaturation. Such cycloalkenyl groups include, by way of example,single ring structures such as cyclohexenyl, cyclopentenyl,cyclopropenyl, and the like.

“Fused cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Nitrogen-containing heterocyclyl” group means a 4- to 7-memberednon-aromatic cyclic group containing at least one nitrogen atom, forexample, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline,imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methyl piperazine. Particular examples includeazetidine, piperidone and piperazone.

“Thioketo” refers to the group ═S.

Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylgroups, as defined herein, are optionally substituted (e.g.,“substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted”alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or“unsubstituted” carbocyclyl, “substituted” or “unsubstituted”heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or“unsubstituted” heteroaryl group). In general, the term “substituted”,whether preceded by the term “optionally” or not, means that at leastone hydrogen present on a group (e.g., a carbon or nitrogen atom) isreplaced with a permissible substituent, e.g., a substituent which uponsubstitution results in a stable compound, e.g., a compound which doesnot spontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction. Unless otherwise indicated,a “substituted” group has a substituent at one or more substitutablepositions of the group, and when more than one position in any givenstructure is substituted, the substituent is either the same ordifferent at each position. The term “substituted” is contemplated toinclude substitution with all permissible substituents of organiccompounds, any of the substituents described herein that results in theformation of a stable compound. The present invention contemplates anyand all such combinations in order to arrive at a stable compound. Forpurposes of this invention, heteroatoms such as nitrogen may havehydrogen substituents and/or any suitable substituent as describedherein which satisfy the valencies of the heteroatoms and results in theformation of a stable moiety.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa), —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa),—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa), —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —SO₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)₂R^(aa), —OP(═O)₂R^(aa), —P(═O)(R^(aa))₂,—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —P(═O)₂N(R^(bb))₂,—OP(═O)₂N(R^(bb))₂, —P(═O)(NR^(bb))₂, —OP(═O)(NR^(bb))₂,—NR^(bb)P(═O)(OR^(cc))₂, —NR^(bb)P(═O)(NR^(bb))₂, —P(R^(cc))₂,—P(R^(cc))₃, —OP(R^(cc))₂, —OP(R^(cc))₃, —B(R^(cc))₂, —B(OR^(cc))₂,—BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa), ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc);

each instance of R^(aa) is, independently, selected from C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl,3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, ortwo R^(aa) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂,—SO₂R^(cc), —SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂,—P(═O)(NR^(cc))₂, C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and5-14 membered heteroaryl, or two R^(bb) groups are joined to form a 3-14membered heterocyclyl or 5-14 membered heteroaryl ring, wherein eachalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroarylis independently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ff))N(R^(ff))₂,—OC(═NR^(ff))N(R^(ff))₂, —NR^(ff)C(═NR^(ff))N(R^(ff))₂,—NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂, —SO₂R^(ee), —SO₂OR^(ee), —OSO₂R^(ee),—S(═O)R^(ee), —Si(R^(ee))₃, —OSi(R^(ee))₃, —C(═S)N(R^(ff))₂,—C(═O)SR^(ee), —C(═S)SR^(ee), —SC(═S)SR^(ee), —P(═O)₂R^(ee),—P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂, —OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, 3-10membered heterocyclyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ -alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₁₀ carbocyclyl,3-10 membered heterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, ortwo R^(ff) groups are joined to form a 3-14 membered heterocyclyl or5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5R^(gg) groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃-C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)₂(C₁₋₆alkyl), —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻²sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substitutents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”), and also contemplates an action that occursbefore a subject begins to suffer from the specified disease, disorderor condition (“prophylactic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease, disorder or condition, or one or more symptoms associated withthe disease, disorder or condition, or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the disease,disorder or condition. The term “prophylactically effective amount” canencompass an amount that improves overall prophylaxis or enhances theprophylactic efficacy of another prophylactic agent.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

The inventors of the present invention, during an on-going explorationof Org-1 analogs for NMDA modulation, a portion of which is described inPCT/US2012/054261, incorporated herein by reference, discovered severalspecific combination of elements which provides NMDA modulators withcomparatively superior properties. For example, as shown in Table 1,compounds bearing a beta-hydrogen at C₅ are disfavored compared tocompounds bearing either alpha-hydrogen C₅ or double bond across C₅-C₆due to loss of potentiation of the NMDA receptor. The removal of themethyl at C₂₁ also results in significant loss of NMDA potentiation.Disubstitution at C₃ is expected to increase metabolic stability ofthese compounds and is thus a preferrred feature of the invention.Fluorination on the C₁₇ side chain has been shown to improve potency andlimit maximum potentiation of the NMDA receptor when tested as high as 1μM concentration of compound. A secondary or tertiary terminal alcoholon the C₁₇ side chain has been shown to improve potency and limitmaximum potentiation of the NMDA receptor when tested as high as 1 μMconcentration of compound, and is thus a preferred feature of theinvention, with a preference for bulkier groups at the terminating endcontaining 2-3 carbons, or a group comprising fluorine substitution.Such properties are expected limit the risk of inducing glutamate drivenneurotoxicity relative to compounds that achieve a greater maximumpotentiation of the NMDA receptor. Compounds of the present inventionencompass various combinations of these specified features to providesuperior NMDA modulators.

Compounds

In one aspect, provided herein are compounds according to Formula (I):

and pharmaceutically acceptable salts thereof;

R¹ is substituted or unsubstituted aliphatic;

R² is hydrogen, halogen, substituted or unsubstituted C₁₋₆alkyl,substituted or unsubstituted cyclopropyl, or —OR^(A2), wherein R^(A2) ishydrogen or substituted or unsubstituted alkyl;

R^(3a) is hydrogen or —OR^(A3), wherein R^(A3) is hydrogen orsubstituted or unsubstituted alkyl, and R^(3b) is hydrogen; or R^(3a)and R^(3b) are joined to form an oxo (═O) group;

R⁴ is hydrogen, substituted or unsubstituted alkyl, or halogen;

X is —C(R^(X))₂— or —O—, wherein R^(X) is hydrogen or fluorine, or oneR^(X) group and R^(5b) are joined to form a double bond;

each instance of R^(5a) and R^(5b) is independently hydrogen orfluorine;

R^(6a) is a non-hydrogen group selected from the group consisting ofsubstituted and unsubstituted alkyl, substituted and unsubstitutedalkenyl, substituted and unsubstituted alkynyl, substituted andunsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl,substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl group, wherein the non-hydrogen group is optionallysubstituted with fluorine; and

R^(6b) is hydrogen or a substituted or unsubstituted alkyl groupoptionally substituted with fluorine;

represents a single or double bond, provided if a single bond ispresent, then the hydrogen at C5 is in the alpha configuration;

and further provided that:

(1) at least one of R^(X), R^(5a), and R^(5b) is fluorine; or

(2) at least one of R^(6a) and R^(6b) is a non-hydrogen groupsubstituted with a fluorine; or

(3) R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms.

As generally described herein, compounds wherein the hydrogen at C₅ isprovided in the beta configuration demonstrate loss of NMDA potentiationcompared to compounds wherein the hydrogen at C₅ is alpha, or wherein adouble bond is present at C₅-C₆. Thus, the compound of Formula (I)encompasses only compounds of Formula (I-A) and (I-B):

and pharmaceutically acceptable salts thereof.

Group R¹

As generally defined herein, R¹ is substituted or unsubstitutedaliphatic, i.e., substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, orsubstituted or unsubstituted carbocyclyl.

In certain embodiments, R¹ is substituted or unsubstituted alkyl, e.g.,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedC₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl, substituted orunsubstituted C₄alkyl, substituted or unsubstituted C₄₋₅alkyl, orsubstituted or unsubstituted C₅₋₆alkyl. Exemplary R¹C₁₋₆alkyl groupsinclude, but are not limited to, substituted or unsubstituted methyl(C₁), ethyl (C₂), n-propyl (C₃), isopropyl (C₃), n-butyl (C₄),tert-butyl (C₄), sec-butyl (C₄), iso-butyl (C₄), n-pentyl (C₅),3-pentanyl (C₅), amyl (C₅), neopentyl (C₅), 3-methyl-2-butanyl (C₅),tertiary amyl (C₅), n-hexyl (C₆), C₁₋₆ alkyl substituted with 1, 2, 3,4, 5, 6, 7, 8, 9, 10, or more fluoro groups (e.g., —CF₃, —CH₂F, —CHF₂,difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C₁₋₆ alkylsubstituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups(e.g., —CH₂Cl, —CHCl₂), and C₁₋₆ alkyl substituted with alkoxy groups(e.g., —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂O-cyclopropyl). In certainembodiments, R¹ is substituted alkyl, e.g., R¹ is haloalkyl,alkoxyalkyl, or aminoalkyl. In certain embodiments, R¹ is Me, Et, n-Pr,n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl,trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl,methoxymethyl, methoxyethyl, or ethoxymethyl.

In certain embodiments, R¹ is unsubstituted C₁₋₃ alkyl, e.g., R¹ is—CH₃, —CH₂CH₃, or —CH₂CH₂CH₃.

In certain embodiments, R¹ is alkyl substituted with one or morefluorine atoms; e.g., R¹ is —CH₂F, —CHF₂, or —CF₃.

In certain embodiments, R¹ is alkyl substituted with one or more—OR^(A1) groups, wherein R^(A1) is hydrogen or substituted orunsubstituted alkyl. In certain embodiments, R¹ is —CH₂OR^(A1), e.g.,wherein R^(A1) is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃.

In certain embodiments, R¹ is substituted or unsubstituted alkenyl,e.g., substituted or unsubstituted C₂₋₆alkenyl, substituted orunsubstituted C₂₋₃alkenyl, substituted or unsubstituted C₃₋₄alkenyl,substituted or unsubstituted C₄₋₅alkenyl, or substituted orunsubstituted C₅₋₆alkenyl. In certain embodiments, R¹ is ethenyl (C₂),propenyl (C₃), or butenyl (C₄), unsubstituted or substituted with one ormore substituents selected from the group consisting of alkyl, halo,haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R¹ isethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl,halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R¹ isethenyl.

In certain embodiments, R¹ is substituted or unsubstituted alkynyl,e.g., substituted or unsubstituted C₂₋₆alkynyl, substituted orunsubstituted C₂₋₃alkynyl, substituted or unsubstituted C₃₋₄alkynyl,substituted or unsubstituted C₄₋₅alkynyl, or substituted orunsubstituted C₅₋₆alkynyl. Exemplary substituted or unsubstituted R¹alkynyl groups include, but are not limited to, ethynyl, propynyl, orbutynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e.g.,CF₃), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), orhydroxyl. In certain embodiments, R¹ is selected from the groupconsisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl,and propynyl, fluoropropynyl, and chloroethynyl. In certain embodiments,R¹ is ethynyl (C₂), propynyl (C₃), or butynyl (C₄), unsubstituted orsubstituted with one or more substituents selected from the groupconsisting of substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, andsubstituted or unsubstituted heterocyclyl. In certain embodiments, R¹ isethynyl (C₂), propynyl (C₃), or butynyl (C₄) substituted withsubstituted phenyl. In certain embodiments, the phenyl substitutent isfurther substituted with one or more substituents selected from thegroup consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino oramido. In certain embodiments, R¹ is ethynyl (C₂), propynyl (C₃), orbutynyl (C₄) substituted with substituted or unsubstituted pyrrolyl,imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl,1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl.

In certain embodiments, R¹ is ethynyl, propynyl, or butynyl,unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl,or hydroxyl. In certain embodiments, R¹ is ethynyl or propynyl,substituted with substituted or unsubstituted aryl. In certainembodiments, R¹ is ethynyl or propynyl, substituted with phenylunsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl,trihaloalkyl, or acyl. In certain embodiments, R¹ is ethynyl orpropynyl, substituted with substituted or unsubstituted carbocyclyl. Incertain embodiments, R^(3a) is ethynyl or propynyl, substituted withsubstituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R¹ is ethynyl or propynyl,substituted with substituted or unsubstituted heteroaryl. In certainembodiments, R¹ is ethynyl or propynyl, substituted with substituted orunsubstituted pyridinyl, or pyrimidinyl. In certain embodiments, R¹ isethynyl or propynyl, substituted with substituted or unsubstitutedpyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl.In certain embodiments, R¹ is ethynyl or propynyl, substituted withsubstituted or unsubstituted heterocyclyl. In certain embodiments, R¹ isethynyl or propynyl, substituted with substituted or unsubstitutedpyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In certainembodiments, R¹ is propynyl or butynyl, substituted with hydroxyl oralkoxy. In certain embodiments, R¹ is propynyl or butynyl, substitutedwith methoxy or ethoxy. In certain embodiments, R¹ is ethynyl orpropynyl, substituted with chloro. In certain embodiments, R¹ is ethynylor propynyl, substituted with trifluoromethyl.

In certain embodiments, R¹ is substituted or unsubstituted carbocyclyl,e.g., substituted or unsubstituted C₃₋₆carbocyclyl, substituted orunsubstituted C₃₋₄carbocyclyl, substituted or unsubstituted C₄₋₅carbocyclyl, or substituted or unsubstituted C₅₋₆ carbocyclyl. Incertain embodiments, R¹ is substituted or unsubstituted cyclopropyl orsubstituted or unsubstituted cyclobutyl.

Groups R², R^(3a), R^(3b), and R⁴

As generally defined herein, R² is hydrogen, halogen, substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted cyclopropyl, or—OR^(A2), wherein R^(A2) is hydrogen or substituted or unsubstitutedalkyl. In certain embodiments, R² is hydrogen. In certain embodiments,R² is halogen, e.g., fluoro, chloro, bromo, or iodo. In certainembodiments, R² is fluoro or chloro. In certain embodiments, R² issubstituted or unsubstituted C₁₋₆alkyl, e.g., substituted orunsubstituted C₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl,substituted or unsubstituted C₃₋₄alkyl, substituted or unsubstitutedC₄₋₅alkyl, or substituted or unsubstituted C₅₋₆alkyl. In certainembodiments, R² is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, or cyclopropyl. In certainembodiments, R² is —OR^(A2). In certain embodiments, R^(A2) is hydrogen.In certain embodiments, R^(A2) is substituted or unsubstituted alkyl,e.g., substituted or unsubstituted C₁₋₆alkyl, substituted orunsubstituted C₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl,substituted or unsubstituted C₃₋₄alkyl, substituted or unsubstitutedC₄₋₅alkyl, or substituted or unsubstituted C₅₋₆alkyl. In certainembodiments, R^(A2) is hydrogen, —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, i.e., toprovide a group R² of formula —OH, —OCH₃, —OCH₂CH₃, or —OCH₂CH₂CH₃. Incertain embodiments, R² is a non-hydrogen substitutent in the alphaconfiguration. In certain embodiments, R² is a non-hydrogen substituentin the beta configuration.

As generally defined herein, R^(3a) is hydrogen or —OR^(A3), whereinR^(A3) is hydrogen or substituted or unsubstituted alkyl, and R^(3b) ishydrogen; or R^(3a) and R^(3b) are joined to form an oxo (═O) group.

In certain embodiments, both R^(3a) and R^(3b) are both hydrogen.

In certain embodiments, R^(3a) and R^(3b) are joined to form an oxo (═O)group.

In certain embodiments, R^(3a) is —OR^(A3) and R^(3b) is hydrogen. Incertain embodiments, wherein R^(3a) is —OR^(A3), R^(3a) is in the alphaor beta configuration. In certain embodiments, wherein R^(3a) is—OR^(A3), R^(3a) is in the alpha configuration. In certain embodiments,wherein R^(3a) is —OR^(A3), R^(3a) is in the beta configuration. Incertain embodiments, R^(A3) is hydrogen. In certain embodiments, R^(A3)is substituted or unsubstituted alkyl, e.g., substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₁₋₂alkyl,substituted or unsubstituted C₂₋₃alkyl, substituted or unsubstitutedC₃₋₄alkyl, substituted or unsubstituted C₄₋₅alkyl, or substituted orunsubstituted C₅₋₆alkyl. In certain embodiments, R^(A3) is hydrogen,—CH₃, —CH₂CH₃, or —CH₂CH₂CH₃, i.e., to provide a group R^(3a) of formula—OH, —OCH₃, —OCH₂CH₃, or —OCH₂CH₂CH₃.

As generally defined herein, R⁴ is hydrogen, substituted orunsubstituted alkyl, or halogen. In certain embodiments, R⁴ is hydrogen.In certain embodiments, R⁴ is halogen, e.g., fluoro. In certainembodiments, R⁴ is substituted or unsubstituted alkyl, e.g., substitutedor unsubstituted C₁₋₆alkyl, substituted or unsubstituted C₁₋₂alkyl,substituted or unsubstituted C₂₋₃alkyl, substituted or unsubstitutedC₃₋₄alkyl, substituted or unsubstituted C₄₋₅alkyl, or substituted orunsubstituted C₅₋₆alkyl. In certain embodiments, R⁴ is C₁ alkyl, e.g.,—CH₃ or —CF₃. In certain embodiments, R⁴ is hydrogen, —CH₃, or —F. Incertain embodiments, wherein

represents a single bond, R⁴ is a non-hydrogen substitutent in the alphaconfiguration. In certain embodiments, wherein

represents a single bond, R⁴ is a non-hydrogen substituent in the betaconfiguration.

Group X, R^(5a), R^(5b), R^(6a), and R^(6b)

As generally defined herein, X is —C(R^(X))₂— or —O—, wherein R^(X) ishydrogen or fluorine, or one R^(X) group and R^(5b) are joined to form adouble bond; each of R^(5a) and R^(5b) is independently hydrogen orfluorine; R^(6a) is a non-hydrogen group selected from the groupconsisting of substituted and unsubstituted alkyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkynyl,substituted and unsubstituted carbocyclyl, substituted and unsubstitutedheterocyclyl, substituted and unsubstituted aryl, and substituted andunsubstituted heteroaryl group, wherein the non-hydrogen group isoptionally substituted with fluorine; and R^(6b) is hydrogen or asubstituted or unsubstituted alkyl group optionally substituted withfluorine; provided: (1) at least one of R^(X), R^(5a), and R^(5b) isfluorine; or (2) at least one of R^(6a) and R^(6b) is a non-hydrogengroup substituted with fluorine; or (3) R^(6a) is a non-hydrogen groupcomprising between two and ten carbon atoms.

In certain embodiments, X is —O—. In certain embodiments, X is —CH₂—. Incertain embodiments, X is —CF₂—.

In certain embodiments, at least one of R^(5a) and R^(5b) is hydrogen.In certain embodiments, at least one of R^(5a) and R^(5b) is fluorine.In certain embodiments, R^(5a) and R^(5b) are both hydrogen. In certainembodiments, R^(5a) and R^(5b) are both fluorine. In certainembodiments, R^(X) and R^(5b) are joined to form a double bond, e.g.,cis or trans double bond.

In certain embodiments, R^(6a) is a non-hydrogen group, as describedherein, which is not substituted with fluorine. In certain embodiments,R^(6a) is substituted or unsubstituted alkyl (e.g., —CH₃, —CH₂CH₃,—CH(CH₃)₂), substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, or substituted or unsubstituted carbocyclyl(e.g., isopropanol). In certain embodiments, R^(6a) is a non-hydrogengroup, as described herein, which is substituted with fluorine.

In certain embodiments, R^(6a) is a non-hydrogen group, as describedherein, and R^(6b) is hydrogen. In certain embodiments, R^(6a) is anon-hydrogen group, as described herein, and R^(6b) is a substituted orunsubstituted alkyl group optionally substituted by fluorine. In certainembodiments, R^(6b) is an alkyl group which is not substituted withfluorine. In certain embodiments, R^(6a) is an alkyl group which issubstituted with fluorine.

In certain embodiments, R^(6b) is hydrogen. In certain embodiments,R^(6b) is substituted or unsubstituted alkyl, e.g., substituted orunsubstituted C₁₋₆alkyl, substituted or unsubstituted C₁₋₂alkyl,substituted or unsubstituted C₂₋₃alkyl, substituted or unsubstitutedC₃₋₄alkyl, substituted or unsubstituted C₄₋₅alkyl, or substituted orunsubstituted C₅₋₆alkyl, optionally substituted by fluorine. In certainembodiments, R^(6b) is C₁ alkyl optionally substituted by fluorine,e.g., —CH₃ or —CF₃.

In certain embodiments, R^(6a) is substituted or unsubstituted alkyl,e.g., substituted or unsubstituted C₁₋₆alkyl, substituted orunsubstituted C₁₋₂alkyl, substituted or unsubstituted C₂₋₃alkyl,substituted or unsubstituted C₃₋₄alkyl, substituted or unsubstitutedC₄₋₅alkyl, or substituted or unsubstituted C₅₋₆alkyl. Exemplary R^(6a)C₁₋₆alkyl groups include, but are not limited to, substituted orunsubstituted methyl (C₁), substituted or unsubstituted ethyl (C₂),substituted or unsubstituted n-propyl (C₃), substituted or unsubstitutedisopropyl (C₃), substituted or unsubstituted n-butyl (C₄), substitutedor unsubstituted tert-butyl (C₄), substituted or unsubstituted sec-butyl(C₄), substituted or unsubstituted iso-butyl (C₄), substituted orunsubstituted n-pentyl (C₅), substituted or unsubstituted 3-pentanyl(C₅), substituted or unsubstituted amyl (C₅), substituted orunsubstituted neopentyl (C₅), substituted or unsubstituted3-methyl-2-butanyl (C₅), substituted or unsubstituted tertiary amyl(C₅), substituted or unsubstituted n-hexyl (C₆). In certain embodiments,R^(6a) is alkyl, as described above, substituted with one or morefluorines, e.g., 1, 2, 3, 4, or more fluorines. In certain embodiments,R^(6a) is —CF₃, —CH₂F, —CHF₂, difluoroethyl, or2,2,2-trifluoro-1,1-dimethyl-ethyl). In certain embodiments, R^(6a) isalkyl, as described above, substituted with one or more —OR^(A6) groups,wherein R^(A6) is hydrogen or substituted or unsubstituted alkyl. Incertain embodiments, R^(6a) is —CH₂OR^(A6), —H₂CH₂OR^(A6), or—CH₂CH₂CH₂OR^(A6), e.g., —CH₂OCH₃, —CH₂CH₂OCH₃, or —CH₂CH₂CH₂OCH₃.

In certain embodiments, R^(6a) is substituted or unsubstituted alkenyl,e.g., substituted or unsubstituted C₂₋₆alkenyl, substituted orunsubstituted C₂₋₃alkenyl, substituted or unsubstituted C₃₋₄alkenyl,substituted or unsubstituted C₄₋₅alkenyl, or substituted orunsubstituted C₅₋₆alkenyl, optionally substituted with fluorine. Incertain embodiments, R^(6a) is substituted or unsubstituted vinyl (C₂)or substituted or unsubstituted allyl (C₃).

In certain embodiments, R^(6a) is substituted or unsubstituted alkynyl,e.g., substituted or unsubstituted C₂₋₆alkynyl, substituted orunsubstituted C₂₋₃alkynyl, substituted or unsubstituted C₃₋₄alkynyl,substituted or unsubstituted C₄₋₅alkynyl, or substituted orunsubstituted C₅₋₆alkynyl, optionally substituted with fluorine. Incertain embodiments, R^(6a) is substituted or unsubstituted ethynyl (C₂)or substituted or unsubstituted propargyl (C₃).

In certain embodiments, R^(6a) is substituted or unsubstitutedcarbocyclyl, e.g., substituted or unsubstituted C₃₋₆carbocyclyl,substituted or unsubstituted C₃₋₄carbocyclyl, substituted orunsubstituted C₄₋₅ carbocyclyl, or substituted or unsubstituted C₅₋₆carbocyclyl, optionally substituted with fluorine. In certainembodiments, R^(6a) is substituted or unsubstituted cyclopropyl.

In certain embodiments, R^(6a) is substituted or unsubstitutedheterocyclyl, e.g., substituted or unsubstituted C₃₋₆ heterocyclyl,substituted or unsubstituted C₃₋₄ heterocyclyl, substituted orunsubstituted C₄₋₅ heterocyclyl, or substituted or unsubstituted C₅₋₆heterocyclyl, optionally substituted with fluorine.

In certain embodiments, R^(6a) is substituted or unsubstituted aryl,e.g., substituted or unsubstituted phenyl, optionally substituted withfluorine.

In certain embodiments, R^(6a) is substituted or unsubstitutedheteroaryl, e.g., optionally substituted 5- to 6-membered heteroaryl,optionally substituted with fluorine.

In certain embodiments, R^(6a) is a non-hydrogen group comprisingbetween two and ten carbon atoms, e.g., between two and nine, two andeight, two and seven, two and six, two and five, two and four, or twoand three carbon atoms, inclusive. For example, in certain embodiments,R^(6a) is substituted or unsubstituted C₂₋₃ alkyl, substituted orunsubstituted C₂₋₃ alkenyl, substituted or unsubstituted C₂₋₃ alkynyl,or substituted or unsubstituted C₃ carbocyclyl.

In certain embodiments, wherein at least one of R^(X), R^(5a), andR^(5b) is fluorine; or at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine; R^(6a) is substituted orunsubstituted C₁₋₃ alkyl, substituted or unsubstituted C₁₋₃ alkenyl,substituted or unsubstituted C₁₋₃ alkynyl, or substituted orunsubstituted C₃ carbocyclyl.

In certain embodiments, R^(6a) and R^(6b) are the same group. In certainembodiments, R^(6a) and R^(6b) are different groups, and the carbon toR^(6a) is attached is in the (S) or (R) configuration. In certainembodiments, the carbon to which R^(6a) is attached is in the (S)configuration. In certain embodiments, the carbon to which R^(6a) isattached is in the (R) configuration. In certain embodiments, R^(6a) is—CF₃ and R^(6b) is hydrogen or C₁₋₄ alkyl. In certain embodiments,R^(6a) is a non-hydrogen group substituted with fluorine, and R^(6b) is—CH₃. In certain embodiments, R^(6a) is substituted with one or more—OR^(A6) groups, wherein R^(A6) is hydrogen or substituted orunsubstituted alkyl. In certain embodiments, R^(6a) is a substituted orunsubstituted C₂₋₄ alkyl, substituted or unsubstituted C₂₋₃ alkenyl,substituted or unsubstituted C₂₋₃ alkynyl, or substituted orunsubstituted C₃ carbocyclyl, and R^(6b) is —CH₃. In certainembodiments, R^(6a) is a unsubstituted C₂₋₄ alkyl, unsubstituted C₂₋₃alkenyl, or unsubstituted C₂₋₃ alkynyl, or unsubstituted C₃ carbocyclyl,and R^(6b) is —CH₃. In certain embodiments, R^(6a) is a non-hydrogengroup substituted with fluorine, and R^(6b) is —CH₃.

Various Combinations of Certain Embodiments

Various combinations of certain embodiments are further contemplatedherein.

For example, in certain embodiments, wherein X is —CH₂— and R^(5a) andR^(5b) are both hydrogen, provided is a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms. In certain embodiments, at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine. In certain embodiments,the carbon to which R^(6a) is attached is in the (S) configuration. Incertain embodiments, the carbon to which R^(6a) is attached is in the(R) configuration. In certain embodiments, R^(6a) is methyl (C₁)optionally substituted with one or more fluorines, e.g., —CH₃ or —CF₃.In certain embodiments, R^(6a) is substituted or unsubstituted ethyl(C₂), substituted or unsubstituted n-propyl (C₃), or substituted orunsubstituted isopropyl (C₃). In certain embodiments, R^(6a) is—CH₂OR^(A6), —CH₂CH₂OR^(A6), or —CH₂CH₂CH₂OR^(A6). In certainembodiments, R^(6a) is substituted or unsubstituted vinyl (C₂) orsubstituted or unsubstituted allyl (C₃). In certain embodiments, R^(6a)is substituted or unsubstituted ethynyl (C₂) or substituted orunsubstituted propargyl (C₃). In certain embodiments, R^(6a) issubstituted or unsubstituted cyclopropyl. In certain embodiments, R^(6b)is hydrogen. In certain embodiments, R^(6b) is —CH₃ or —CF₃. In certainembodiments,

represents a single bond, and the hydrogen at C5 is alpha. In certainembodiments,

represents a double bond. In certain embodiments, R¹ is —CH₃ or —CH₂CH₃.In certain embodiments, R² is hydrogen, —OH, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, cyclopropyl, fluoro, or chloro.In certain embodiments, R² is a non-hydrogen substitutent in the alphaconfiguration. In certain embodiments, R² is a non-hydrogen substituentin the beta configuration. In certain embodiments, R^(3a) and R^(3b) areboth hydrogen. In certain embodiments, R^(3a) and R^(3b) are joined toform ═O (oxo). In certain embodiments, R⁴ is hydrogen.

In certain embodiments, wherein X is —CH₂— and R^(5a) and R^(5b) areboth fluorine, provided is a compound of Formula (I-b):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms. In certain embodiments, at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine. In certain embodiments,the carbon to which R^(6a) is attached is in the (S) configuration. Incertain embodiments, the carbon to which R^(6a) is attached is in the(R) configuration. In certain embodiments, R^(6a) is methyl (C₁),optionally substituted with one or more fluorines, e.g., —CH₃ or —CF₃.In certain embodiments, R^(6a) is substituted or unsubstituted ethyl(C₂), substituted or unsubstituted n-propyl (C₃), or substituted orunsubstituted isopropyl (C₃). In certain embodiments, R^(6a) is—CH₂OR^(A6), —CH₂CH₂OR^(A6), or —CH₂CH₂CH₂OR^(A6). In certainembodiments, R^(6a) is substituted or unsubstituted vinyl (C₂) orsubstituted or unsubstituted allyl (C₃). In certain embodiments, R^(6a)is substituted or unsubstituted ethynyl (C₂) or substituted orunsubstituted propargyl (C₃). In certain embodiments, R^(6a) issubstituted or unsubstituted cyclopropyl. In certain embodiments, R^(6b)is hydrogen. In certain embodiments, R^(6b) is —CH₃ or —CF₃. In certainembodiments,

represents a single bond, and the hydrogen at C5 is alpha. In certainembodiments,

represents a double bond. In certain embodiments, R¹ is —CH₃ or —CH₂CH₃In certain embodiments, R² is hydrogen, —OH, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, cyclopropyl, fluoro, or chloro.In certain embodiments, R² is a non-hydrogen substitutent in the alphaconfiguration. In certain embodiments, R² is a non-hydrogen substituentin the beta configuration. In certain embodiments, R^(3a) and R^(3b) areboth hydrogen. In certain embodiments, R^(3a) and R^(3b) are joined toform ═O (oxo). In certain embodiments, R⁴ is hydrogen.

In certain embodiments, wherein X is —C(R^(X))₂— and one R^(X) group andR^(5b) are joined to form a trans double bond, provided is a compound ofFormula (I-c):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms. In certain embodiments, at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine. In certain embodiments,the carbon to which R^(6a) is attached is in the (S) configuration. Incertain embodiments, the carbon to which R^(6a) is attached is in the(R) configuration. In certain embodiments, R^(6a) is methyl (C₁)optionally substituted with one or more fluorines, e.g., —CH₃ or —CF₃.In certain embodiments, R^(6a) is substituted or unsubstituted ethyl(C₂), substituted or unsubstituted n-propyl (C₃), or substituted orunsubstituted isopropyl (C₃). In certain embodiments, R^(6a) is—CH₂OR^(A6), —CH₂CH₂OR^(A6), or —CH₂CH₂CH₂OR^(A6). In certainembodiments, R^(6a) is substituted or unsubstituted vinyl (C₂) orsubstituted or unsubstituted allyl (C₃). In certain embodiments, R^(6a)is substituted or unsubstituted ethynyl (C₂) or substituted orunsubstituted propargyl (C₃). In certain embodiments, R^(6a) issubstituted or unsubstituted cyclopropyl. In certain embodiments, R^(6b)is hydrogen. In certain embodiments, R^(6b) is —CH₃ or —CF₃. In certainembodiments,

represents a single bond, and the hydrogen at C5 is alpha. In certainembodiments,

represents a double bond. In certain embodiments, R¹ is —CH₃ or —CH₂CH₃.In certain embodiments, R² is hydrogen, —OH, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, cyclopropyl, fluoro, or chloro.In certain embodiments, R² is a non-hydrogen substitutent in the alphaconfiguration. In certain embodiments, R² is a non-hydrogen substituentin the beta configuration. In certain embodiments, R^(3a) and R^(3b) areboth hydrogen. In certain embodiments, R^(3a) and R^(3b) are joined toform ═O (oxo). In certain embodiments, R⁴ is hydrogen.

In certain embodiments, the compound of Formula (I) is selected from acompound of Formula (II):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms. In certain embodiments, at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine. In certain embodiments,the carbon to which R^(6a) is attached is in the (S) configuration. Incertain embodiments, the carbon to which R^(6a) is attached is in the(R) configuration. In certain embodiments, R^(6a) is methyl (C₁)optionally substituted with one or more fluorines, e.g., —CH₃ or —CF₃.In certain embodiments, R^(6a) is substituted or unsubstituted ethyl(C₂), substituted or unsubstituted n-propyl (C₃), or substituted orunsubstituted isopropyl (C₃). In certain embodiments, R^(6a) is—CH₂OR^(A6), —CH₂CH₂OR^(A6), or —CH₂CH₂CH₂OR^(A6). In certainembodiments, R^(6a) is substituted or unsubstituted vinyl (C₂) orsubstituted or unsubstituted allyl (C₃). In certain embodiments, R^(6a)is substituted or unsubstituted ethynyl (C₂) or substituted orunsubstituted propargyl (C₃). In certain embodiments, R^(6a) issubstituted or unsubstituted cyclopropyl. In certain embodiments, R^(6b)is hydrogen. In certain embodiments, R^(6b) is —CH₃ or —CF₃. In certainembodiments,

represents a single bond, and the hydrogen at C5 is alpha. In certainembodiments,

represents a double bond. In certain embodiments, R¹ is —CH₃ or —CH₂CH₃.

In certain embodiments, the compound of Formula (I) is selected from acompound of Formula (II-A):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms. In certain embodiments, at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine. In certain embodiments,the carbon to which R^(6a) is attached is in the (S) configuration. Incertain embodiments, the carbon to which R^(6a) is attached is in the(R) configuration. In certain embodiments, R^(6a) is methyl (C₁)optionally substituted with one or more fluorines, e.g., —CH₃ or —CF₃.In certain embodiments, R^(6a) is substituted or unsubstituted ethyl(C₂), substituted or unsubstituted n-propyl (C₃), or substituted orunsubstituted isopropyl (C₃). In certain embodiments, R^(6a) is—CH₂OR^(A6), —CH₂CH₂OR^(A6), or —CH₂CH₂CH₂OR^(A6). In certainembodiments, R^(6a) is substituted or unsubstituted vinyl (C₂) orsubstituted or unsubstituted allyl (C₃). In certain embodiments, R^(6a)is substituted or unsubstituted ethynyl (C₂) or substituted orunsubstituted propargyl (C₃). In certain embodiments, R^(6a) issubstituted or unsubstituted cyclopropyl. In certain embodiments, R^(6b)is hydrogen. In certain embodiments, R^(6b) is —CH₃ or —CF₃. In certainembodiments, R¹ is —CH₃ or —CH₂CH₃.

In certain embodiments, the compound of Formula (I) is selected from acompound of Formula (II-B):

or a pharmaceutically acceptable salt thereof. In certain embodiments,R^(6a) is a non-hydrogen group comprising between two and ten carbonatoms. In certain embodiments, at least one of R^(6a) and R^(6b) is anon-hydrogen group substituted with fluorine. In certain embodiments,the carbon to which R^(6a) is attached is in the (S) configuration. Incertain embodiments, the carbon to which R is attached is in the (R)configuration. In certain embodiments, R^(6a) is methyl (C₁) optionallysubstituted with one or more fluorines, e.g., —CH₃ or —CF₃. In certainembodiments, R^(6a) is substituted or unsubstituted ethyl (C₂),substituted or unsubstituted n-propyl (C₃), or substituted orunsubstituted isopropyl (C₃). In certain embodiments, R^(6a) is—CH₂OR^(A6), —CH₂CH₂OR^(A6), or —CH₂CH₂CH₂OR^(A6). In certainembodiments, R^(6a) is substituted or unsubstituted vinyl (C₂) orsubstituted or unsubstituted allyl (C₃). In certain embodiments, R^(6a)is substituted or unsubstituted ethynyl (C₂) or substituted orunsubstituted propargyl (C₃). In certain embodiments, R^(6a) issubstituted or unsubstituted cyclopropyl. In certain embodiments, R^(6b)is hydrogen. In certain embodiments, R^(6b) is —CH₃ or —CF₃. In certainembodiments, R¹ is —CH₃ or —CH₂CH₃.

In certain embodiments, a compound of Formula (I) is selected from thegroup consisting of:

and pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions

In another aspect, the invention provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and a effective amountof a compound of Formula (I).

When employed as pharmaceuticals, the compounds provided herein aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

In one embodiment, with respect to the pharmaceutical composition, thecarrier is a parenteral carrier, oral or topical carrier.

The present invention also relates to a compound of Formula (I) orpharmaceutical composition thereof for use as a pharmaceutical or amedicament.

Generally, the compounds provided herein are administered in atherapeutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions provided herein can be administered by avariety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds provided herein are preferablyformulated as either injectable or oral compositions or as salves, aslotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope provided herein.

The compounds provided herein can also be administered by a transdermaldevice. Accordingly, transdermal administration can be accomplishedusing a patch either of the reservoir or porous membrane type, or of asolid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The above-described components for orally administrable, injectable, ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's The Science and Practice of Pharmacy, 21stedition, 2005, Publisher: Lippincott Williams & Wilkins, which isincorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The present invention also relates to the pharmaceutically acceptableformulations of a compound of Formula (I). In one embodiment, theformulation comprises water. In another embodiment, the formulationcomprises a cyclodextrin derivative. The most common cyclodextrins areα-, β- and γ-cyclodextrins consisting of 6, 7 and 8α-1,4-linked glucoseunits, respectively, optionally comprising one or more substituents onthe linked sugar moieties, which include, but are not limited to,methylated, hydroxyalkylated, acylated, and sulfoalkylethersubstitution. In certain embodiments, the cyclodextrin is a sulfoalkylether β-cyclodextrin, e.g., for example, sulfobutyl ether3-cyclodextrin, also known as Captisol®. See, e.g., U.S. Pat. No.5,376,645. In certain embodiments, the formulation compriseshexapropyl-β-cyclodextrin. In a more particular embodiment, theformulation comprises hexapropyl-β-cyclodextrin (10-50% in water).

The present invention also relates to the pharmaceutically acceptableacid addition salt of a compound of Formula (I). The acid which may beused to prepare the pharmaceutically acceptable salt is that which formsa non-toxic acid addition salt, i.e., a salt containingpharmacologically acceptable anions such as the hydrochloride,hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate,acetate, lactate, citrate, tartrate, succinate, maleate, fumarate,benzoate, para-toluenesulfonate, and the like.

The following formulation examples illustrate representativepharmaceutical compositions that may be prepared in accordance with thisinvention. The present invention, however, is not limited to thefollowing pharmaceutical compositions.

Exemplary Formulation 1—Tablets:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 240-270 mg tablets(80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2—Capsules:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a starch diluent in an approximate1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg ofactive compound per capsule).

Exemplary Formulation 3—Liquid:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,(125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) andthe resultant mixture may be blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously made solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water may then be addedto produce a total volume of 5 mL.

Exemplary Formulation 4—Tablets:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 450-900 mg tablets(150-300 mg of active compound) in a tablet press.

Exemplary Formulation 5—Injection:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be dissolved or suspended in a buffered sterile saline injectableaqueous medium to a concentration of approximately 5 mg/mL.

Exemplary Formulation 6—Tablets:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 90-150 mg tablets(30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7—Tablets:

v may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 30-90 mg tablets (10-30mg of active compound per tablet) in a tablet press.

Exemplary Formulation 8—Tablets:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 0.3-30 mg tablets(0.1-10 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 9—Tablets:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 150-240 mg tablets(50-80 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 10—Tablets:

A compound of Formula (I), or pharmaceutically acceptable salt thereof,may be admixed as a dry powder with a dry gelatin binder in anapproximate 1:2 weight ratio. A minor amount of magnesium stearate isadded as a lubricant. The mixture is formed into 270-450 mg tablets(90-150 mg of active compound per tablet) in a tablet press.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions the regimenfor treatment usually stretches over many months or years so oral dosingis preferred for patient convenience and tolerance. With oral dosing,one to five and especially two to four and typically three oral dosesper day are representative regimens. Using these dosing patterns, eachdose provides from about 0.01 to about 20 mg/kg of the compound providedherein, with preferred doses each providing from about 0.1 to about 10mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a CNS-disorder, the compounds providedherein will be administered to a subject at risk for developing thecondition, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Subjects at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

Methods of Treatment and Use

Compounds of Formula (I), and pharmaceutically acceptable salts thereof,as described herein, are generally designed to modulate NMDA function,and therefore to act as neuroactive steroids for the treatment andprevention of CNS-related conditions in a subject. Modulation, as usedherein, refers to the inhibition or potentiation of NMDA receptorfunction. In certain embodiments, the compound of Formula (I), orpharmaceutically acceptable salt thereof, may act as a negativeallosteric modulator (NAM) of NMDA, and inhibit NMDA receptor function.In certain embodiments, the compound of Formula (I), or pharmaceuticallyacceptable salt thereof, may act as positive allosteric modulators (PAM)of NMDA, and potentiate NMDA receptor function.

Exemplary CNS conditions related to NMDA-modulation include, but are notlimited to, adjustment disorders, anxiety disorders (includingobsessive-compulsive disorder, posttraumatic stress disorder, socialphobia, generalized anxiety disorder), cognitive disorders (includingAlzheimer's disease and other forms of dementia), dissociativedisorders, eating disorders, mood disorders (including depression,bipolar disorder, and dysthymic disorder), schizophrenia or otherpsychotic disorders (including schizoaffective disorder), sleepdisorders (including insomnia), substance abuse-related disorders,personality disorders (including obsessive-compulsive personalitydisorder), autism spectrum disorders (including those involvingmutations to the Shank group of proteins), neurodevelopmental disorders(including Rett syndrome), pain (including acute and chronic pain),seizure disorders (including status epilepticus and monogenic forms ofepilepsy such as Dravet's disease, and Tuberous Sclerosis Complex(TSC)), stroke, traumatic brain injury, movement disorders (includingHuntington's disease and Parkinson's disease) and tinnitus. In certainembodiments, the compound of Formula (I), or pharmaceutically acceptablesalt thereof, can be used to induce sedation or anesthesia. In certainembodiments, the compound of Formula (I), or pharmaceutically acceptablesalt thereof, is useful in the treatment or prevention of adjustmentdisorders, anxiety disorders, cognitive disorders, dissociativedisorders, eating disorders, mood disorders, schizophrenia or otherpsychotic disorders, sleep disorders, substance-related disorders,personality disorders, autism spectrum disorders, neurodevelopmentaldisorders, pain, seizure disorders, stroke, traumatic brain injury,movement disorders and tinnitus.

In another aspect, provided is a method of treating or preventing brainexcitability in a subject susceptible to or afflicted with a conditionassociated with brain excitability, comprising administering to thesubject an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In yet another aspect, the present invention provides a combination of acompound of Formula (I), or pharmaceutically acceptable salt thereof,and another pharmacologically active agent. The compounds providedherein can be administered as the sole active agent or they can beadministered in combination with other agents. Administration incombination can proceed by any technique apparent to those of skill inthe art including, for example, separate, sequential, concurrent andalternating administration.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

Materials and Methods

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include (but are not limited to)recrystallization, column chromatography, HPLC, or supercritical fluidchromatography (SFC). The following schemes are presented with detailsas to the preparation of representative substituted biarylamides thathave been listed herein. The compounds provided herein may be preparedfrom known or commercially available starting materials and reagents byone skilled in the art of organic synthesis. Exemplary chiral columnsavailable for use in the separation/purification of theenantiomers/diastereomers provided herein include, but are not limitedto, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD,CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ andCHIRALCEL® OK.

General method for supercritical fluid chromatography (SFC): SFCpurification was carried out using a Thar 200 preparative SFC instrumentequipped with a ChiralPak AD-10 μM, 200×50 mm ID. The compounds wereseparated eluting with mixtures of carbon dioxide and methanol orethanol (e.g., 20-35% methanol or ethanol and 0.1% ammonium hydroxide)at a flow rate of 55-200 mL/min and monitored at 220 nm wavelength.

Single pure isomers were obtained after SFC chromatographic separation,yielding two isomers with a diasteriomeric ratio≧95:5, as determined bySFC chromatography.

The configuration of the steroid C-24 stereocenter of 1-13 and 1-14, and2-20 and 2-21 isomers was determined by the Mosher Method (Dale, J. A.,Dull, D. L., and Mosher, H. S. (1969) J. Org. Chem. 34, 2543). The C-24configuration of subsequent derivatives that employed suchintermediates, for example 1-15 and 1-17, were assigned accordingly.

For all other single diastereomers, for which the C-24 stereocenter wasnot determined by the Mosher Method, the first eluting diastereomer fromthe SFC was tentatively assigned to be attached in the (R) configurationat C-24, whereas the second eluting diastereomer from the SFC wastentatively assigned to be attached in the (S) configuration at C-24.The assignments were not unambiguously confirmed by the Mosher Method orother techniques.

Example 1

Preparation of Compound 1-2.

To a solution of ketone 1-1 (50.0 g, 0.17 mol) and ethylene glycol (62mL) in toluene (600 mL) was added p-toluenesulfonic acid (1.4 g, 7.28mmol). The reaction mixture was refluxed overnight with a Dean-Starktrap. The mixture was cooled to room temperature, diluted with ethylacetate (500 mL), and washed with saturated aqueous sodium bicarbonate(300 mL×2) and brine (300 mL×2). The organic phase was dried over sodiumsulfate and concentrated in vacuum to afford crude product 1-2 (64.0 g,100%) which was directly used in the next step without furtherpurification. ¹H NMR: (400 MHz, CDCl3) δ 5.35 (d, J=5.6 Hz, 1H),3.97-3.82 (m, 4H), 3.59-3.47 (m, 1H), 2.34-2.21 (m, 2H), 2.06-1.94 (m,2H), 1.90-1.74 (m, 3H), 1.73-1.64 (m, 1H), 1.63-1.33 (m, 10H), 1.32-1.19(m, 1H), 1.14-1.03 (m, 1H), 1.01 (s, 3H), 0.99-0.93 (m, 1H), 0.86 (s,3H).

Preparation of Compound 1-3.

To a solution of compound 1-2 (32 g, 96 mmol) in dry CH₂Cl₂ (1200 mL)was added Dess-Martin reagent (81 g, 192 mmol) in portions at 0° C. Thenthe reaction mixture was stirred at room temperature for 3 h. TLC(petroleum ether:ethyl acetate=3:1) showed the starting material wasconsumed completely. The mixture was quenched with saturated aqueousNaHCO₃/Na₂S₂O₃=1:3 (1 L). The organic phase was washed with brine (500mL) and dried over Na₂SO₄, and the solvent was evaporated to affordcrude product 1-3 (33.0 g, 100%), which was directly used in the nextstep without further purification. ¹H NMR: (400 MHz, CDCl3) δ 5.34 (d,J=5.2 Hz, 1H), 3.77-4.00 (m, 4H), 3.19-3.39 (m, 1H), 2.83 (dd, J=16.44,2.13 Hz, 1H), 2.38-2.59 (m, 1H), 2.21-2.37 (m, 1H), 1.95-2.09 (m, 3H),1.54-1.73 (m, 4H), 1.74-1.90 (m, 2H), 1.37-1.51 (m, 3H), 1.21-1.34 (m,2H), 1.19 (s, 3H), 0.98-1.12 (m, 1H), 0.83-0.93 (m, 3H).

Preparation of MAD.

To a solution of 2,6-di-tert-butyl-4-methylphenol (40 g, 180 mmol) intoluene (200 mL) was added a solution of AlMe₃ (45 mL, 90 mmol, 2 M inhexane) at room temperature. The resulting mixture was stirred at roomtemperature for 1 h and used as a solution of MAD in toluene in the nextstep without any purification.

Preparation of Compound 1-4.

To a solution of MAD (90 mmol, freshly prepared) in toluene (200 mL) wasadded dropwise a solution of compound 1-3 (10 g, 30 mmol) in toluene (80mL) at −78° C. during a period of 1 h under nitrogen. Then the reactionmixture was stirred for 30 min, a solution of CH₃MgBr (30 mL, 90 mmol,1.0 M in toluene) was added dropwise at −78° C. The reaction mixture waswarmed to −40° C. and stirred at this temperature for 3 h. TLC(petroleum ether:ethyl acetate=3:1) showed that the starting materialwas consumed completely. The mixture was poured into saturated aqueousNH₄Cl solution (200 mL) and extracted with EtOAc (150 mL×2). Thecombined organic phases were dried over Na₂SO₄, and the solvent wasevaporated to afford crude product, which was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=15:1) to give compound 1-4 (4 g, 38%) as white powder. ¹H NMR:(400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H), 3.75-4.04 (m, 4H), 2.42 (d,J=13.6 Hz, 1H), 1.88-2.12 (m, 3H), 1.73-1.86 (m, 2H), 1.64-1.72 (m, 2H),1.52-1.63 (m, 4H), 1.35-1.51 (m, 4H), 1.19-1.32 (m, 1H), 1.12-1.18 (m,1H), 1.10 (s, 3H), 0.99-1.03 (m, 3H), 0.92-0.98 (m, 1H), 0.86 (s, 3H).

Preparation of Compound 1-5.

To a solution of compound 1-4 (6.0 g, 17.3 mmol) in THF (200 mL) wasadded aqueous HCl solution (35 mL, 1 M) and acetone (35 mL). Thereaction mixture was stirred for 20° C. at room temperature. TLC(petroleum ether:ethyl acetate=3:1) indicated that the reaction wascomplete. Then the reaction mixture was diluted with EtOAc (200 mL),washed with saturated aqueous NaHCO₃ solution (200 mL), dried overNa₂SO₄ and evaporated under reduced pressure to give 1-5 (5.2 g, 99.2%).¹H NMR: (400 MHz, CDCl3) δ 5.27 (d, J=6.8 Hz, 1H), 2.45-2.35 (m, 2H),2.09-1.84 (m, 4H), 1.82-1.57 (m, 6H), 1.50-1.35 (m, 4H), 1.26-1.08 (m,4H), 1.05 (s, 3H), 0.95 (s, 3H), 0.86 (s, 3H).

Preparation of Compound 1-6.

To a solution of Ph₃PEtBr (12.25 g, 33.00 mmol) in dry THF (15 mL) wasadded dropwise a solution of t-BuOK (3.70 g, 33.00 mmol) in dry THF (10mL) under N₂ at 0° C. The mixture was stirred at room temperature for1.5 h. Then a solution of 1-5 (1.00 g, 3.31 mmol) in THF (10 mL) wasadded dropwise and the resulting mixture was stirred at 70° C. for 4 h.TLC (petroleum ether:ethyl acetate=3:1) indicated that the startingmaterial was consumed completely. The reaction was quenched withsaturated aqueous NH₄Cl solution (50 mL) and extracted with EtOAc (30mL×2). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=12:1) to give 1-6 (900 mg, 90.9%) as white powder. ¹H NMR: (400MHz, CDCl3) δ 5.32 (d, J=5.2 Hz, 1H), 5.15-5.12 (m, 1H), 2.44-2.30 (m,3H), 2.29-2.21 (m, 1H), 2.05-1.97 (m, 2H), 1.81-1.45 (m, 14H), 1.30-1.15(m, 3H), 1.12 (s, 3H), 1.02 (s, 3H), 0.95-1.01 (m, 1H), 0.90 (s, 3H).

Preparation of Compound 1-7.

To a solution of compound 1-6 (1.00 g, 3.20 mmol) and methyl propiolate(0.67 g, 8.00 mmol) in dry CH₂Cl₂ (15 mL) was added dropwise a solutionof Et₂AlCl (12.8 mL, 12.8 mmol, 1 M in toluene) with stirring at 0° C.Then the reaction was warmed to room temperature and stirred for 20 h.TLC (petroleum ether:ethyl acetate=5:1) indicated that the startingmaterial was consumed completely. The mixture was quenched withsaturated aqueous NaHCO₃ solution (30 mL) and extracted with CH₂Cl₂ (30mL×2). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=10:1) to give 1-7 (1.00 g, 78.7%) as white powder. ¹H NMR: (400MHz, CDCl3) δ 6.97-6.91 (m, 1H) 5.82 (d, J=16 Hz, 1H), 5.42-5.41 (m,1H), 5.32 (d, J=5.2 Hz, 1H), 3.73 (s, 3H), 3.04-3.00 (m, 1H), 2.43 (d,J=12.8 Hz, 1H), 2.11-1.97 (m, 3H), 1.88-1.50 (m, 12H), 1.40-1.20 (m,3H), 1.21-1.26 (m, 1H), 1.18 (d, J=6.78 Hz, 3H), 1.12 (s, 3H), 1.04 (s,3H), 0.82 (s, 3H).

Preparation of Compound 1-8.

To a solution of compound 1-7 (1.75 g, 4.4 mmol) in dry THF (20 mL),DIBAL-H (1 M in THF, 22 mL, 22.0 mmol) was added dropwise at −78° C.under nitrogen. The reaction mixture was warmed to 30° C. and thenstirred for 2 h at 30° C. The reaction was quenched with addition of H₂O(2 mL), diluted with EtOAc (200 mL) and dried over anhydrous Na₂SO₄,filtered through a pad of celite and the pad was washed with EtOAc (50mL×3). The combined filtrates were concentrated in vacuum to give thecrude product 1-8 (1.6 g, 98%) which was directly used in the next stepwithout further purification.

Preparation of Compound 1-9.

A mixture of 1-8 (1.6 g, 4.3 mmol) and MnO₂ (7.5 g, 86.0 mmol) in CH₂Cl₂(50 mL) was stirred at 30° C. for 20 h. The reaction mixture wasfiltered through a pad of celite and the pad was washed with CH₂Cl₂ (50mL×3). The combined filtrates were concentrated to dryness to give thecrude product 1-9 (1.3 g, 82%) which was directly used in the next stepwithout purification. ¹H NMR: (400 MHz, CDCl3) δ 9.54 (d, J=7.6 Hz, 1H),6.84-6.78 (dd, J₁=15.6 Hz, J₂=7.6 Hz, 1H), 5.54-5.49 (dd, J₁=15.6 Hz,J₂=7.6 Hz, 1H), 5.45-5.44 (m, 1H), 5.32 (d, J=5.2 Hz, 1H), 3.19-3.12 (m,1H), 2.42 (d, J=12.8 Hz, 1H), 2.14-2.08 (m, 1H), 2.00-1.52 (m, 13H),1.42-1.35 (m, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.12 (s, 3H), 1.05 (s, 3H),0.80 (s, 3H).

Preparation of Compound 1-10.

To a suspension of 1-9 (600 mg, 1.63 mmol) and CsF (120 mg, 0.82 mmol)in toluene/THF (18 mL, 8/1) was added TMSCF₃ (2.4 mL, 16.3 mmol) and themixture was stirred for 20° C. at room temperature under nitrogen. TLC(petroleum ether:ethyl acetate=3/1) showed the starting material wasconsumed completely. A solution of TBAF (6.8 mL, 1 M in THF) was addedand the mixture was stirred for 4 h at room temperature. The mixture wasdiluted with MTBE (200 mL), washed with a saturated NaHCO₃ solution (30mL×3) and concentrated in vacuum. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=12/1) to afford 1-10 (300 mg, 42%) as white solid. ¹H NMR: (400MHz, CDCl3) δ 5.97-5.91 (dd, J₁=15.6 Hz, J₂=7.6 Hz, 1H), 5.54-5.49 (dd,J₁=15.6 Hz, J₂=6.8 Hz, 1H), 5.42-5.38 (m, 1H), 5.30 (d, J=5.2 Hz, 1H),4.44-4.36 (m, 1H), 2.97-2.94 (m, 1H), 2.42 (d, J=12.0 Hz, 1H), 2.01-1.98(m, 2H), 1.88-1.64 (m, 6H), 1.40-1.32 (m, 3H), 1.26-1.21 (m, 2H), 1.17(d, J=6.8 Hz, 3H), 1.12 (s, 3H), 1.05 (s, 3H), 1.00-0.95 (m, 2H), 0.79(s, 3H).

Preparation of Compound 1-11.

A mixture of 1-10 (40 mg, 0.09 mmol) and 5% Pd/C (10 mg) in EA (10 mL)was hydrogenated for 2 h at 30° C. under 1 atm of hydrogen pressure. Thereaction mixture was filtered through a pad of celite and the pad waswashed with EA (10 mL×3). The combined filtrates were concentrated. Theresidue was purified by column chromatography on silica gel (eluent:PE/EA=8/1) to afford 1-11 (20 mg, 50%) as white solid. ¹H NMR: (400 MHz,CDCl3) δ 5.31 (d, J=5.2 Hz, 1H), 3.87-3.86 (m, 1H), 2.42 (d, J=12.8 Hz,1H), 2.15-2.12 (m, 1H), 2.05-1.96 (m, 3H), 1.86-1.41 (m, 16H), 1.38-1.11(m, 5H), 1.11 (s, 3H), 1.08-1.04 (m, 1H), 1.01 (s, 3H), 0.95 (d, J=6.6Hz, 3H), 0.69 (s, 3H).

Preparation of Compound 1-13 and 1-14.

1-13 (120 mg, 40%) and 1-14 (120 mg, 40%) were obtained by SFCpurification from 1-10 (300 mg, 0.814 mmol). The configuration of 1-13and 1-14 was confirmed by Mosher method.

Preparation of Compound 1-15.

A mixture of 1-13 (120 mg, 0.27 mmol) and 5% Pd/C (20 mg) in EtOAc (10mL) was hydrogenated for 20 h at room temperature under H₂ (1 atm). Thereaction mixture was filtered through a pad of celite and the pad waswashed with EtOAc (10 mL×3). The combined filtrates were concentrated.The residue was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=8/1) to afford 1-15 (70 mg, 59%) as whitepowder. 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H), 4.00-3.90 (m,1H), 2.42 (d, J=13.2 Hz, 1H), 2.02-1.29 (m, 18H), 1.28-1.08 (m, 6H),1.03 (s, 3H), 1.02 (s, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.73 (s, 3H).

Preparation of Compound 1-17.

A mixture of 1-14 (120 mg, 0.27 mmol) and 5% Pd/C (20 mg) in EtOAc (10mL) was hydrogenated for 20 h at room temperature under H₂ (1 atm). Thereaction mixture was filtered through a pad of celite and the pad waswashed with EtOAc (10 mL×3). The combined filtrates were concentrated.The residue was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=8/1) to afford 1-17 (71 mg, 59%) as whitepowder. ¹H NMR: (400 MHz, CDCl3) δ 5.27 (d, J=5.6 Hz, 1H), 4.00-3.90 (m,1H), 2.42 (d, J=13.2 Hz, 1H), 2.03-1.28 (m, 19H), 1.25-1.03 (m, 5H),1.03 (s, 3H), 1.02 (s, 3H), 0.97 (d, J=6.4 Hz, 3H), 0.73 (s, 3H).

Example 2

Preparation of 2-2.

To a solution of MAD (28.87 mmol, freshly prepared) in toluene (20 mL)was added dropwise a solution of 2-1 (4 g, 9.62 mmol) in toluene (20 mL)at −78° C. during a period of 1 h under nitrogen. Then the reactionmixture was stirred for 30 min, a solution of EtMgBr (29 mL, 28.87 mmol,1.0 M in toluene) was added dropwise at −78° C. The reaction mixture waswarmed to −40° C. and stirred at this temperature for 3 hours. TLC(petroleum ether:ethyl acetate=3:1) showed that the starting materialwas consumed completely. The mixture was poured into aqueous saturatedNH₄Cl solution (200 mL) and extracted with EtOAc (150 mL×2). Thecombined organic phases were dried over Na₂SO₄, and the solvent wasevaporated to afford crude product. The crude product was purified bycolumn chromatography on silica gel (eluent: petroleum ether:ethylacetate=15:1) to give the product 2-2 (2.0 g, 47.6%) as white powder. ¹HNMR: (400 MHz, CDCl3) δ 5.28 (d, J=5.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s,3H), 2.45-2.34 (m, 3H), 2.04-1.95 (m, 3H), 1.94-1.61 (m, 4H), 1.62-1.60(m, 2H), 1.53-1.26 (m, 10H), 1.19-1.01 (m, 4H), 1.10 (s, 3H), 0.98-0.90(m, 4H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation of 2-3.

To a suspension of LiAlH₄ (852.6 mg, 22.43 mmol) in THF (20 ml) wasadded 2-2 (2.0 g, 4.48 mmol) at −78° C., then the solution was stirredat −78° C. for 2 hours. The mixture was poured into aqueous saturatedNaOH solution (2 mL) and extracted with EtOAc (50 mL×2). The combinedorganic phases were dried over Na₂SO₄, and the solvent was evaporated toafford crude product. The crude product was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=20:1) to give the product 2-3 (600 mg, 35%) as white powder. ¹HNMR: (400 MHz, CDCl3) δ 9.78 (s, 1H), 5.28 (d, J=5.2 Hz, 1H), 2.51-2.22(m, 3H), 2.03-1.91 (m, 3H), 1.89-1.73 (m, 3H), 1.67-1.61 (m, 2H),1.65-1.629 (m, 1H), 1.50-1.21 (m, 10H), 1.19-1.06 (m, 4H), 1.02 (s, 3H),1.01-0.99 (m, 1H), 0.98-0.93 (m, 4H), 0.87 (t, J=6.8 Hz, 3H), 0.68 (s,3H).

Preparation of 2-4.

To a mixture of 2-3 (0.3 g, 0.78 mmol) and CsF (0.06 g, 0.39 mmol) intoluene/THF (18 mL, 8/1) was added TMSCF₃ (1.2 mL, 7.8 mmol) and thereaction mixture was stirred at room temperature overnight undernitrogen. TLC (petroleum ether:ethyl acetate=3/1) showed the startingmaterial was consumed completely. A solution of TBAF (7.8 mL, 7.8 mmol,1 M in THF) was added and the mixture was stirred for 4 h at roomtemperature. The reaction mixture was diluted with tert-Butyl methylether (30 mL), washed with aq. saturated NaHCO₃ solution (10 mL×3) andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=20:1) to afford 2-4 (80 mg, 22%) as white powder. ¹H NMR: (400MHz, CDCl3) 5.29 (d, J=5.2 Hz, 1H), 3.87-3.84 (m, 1H), 2.36 (d, J=13.2Hz, 1H), 2.05-1.95 (m, 3H), 1.86-1.61 (m, 6H), 1.54-1.06 (m, 17H), 1.03(s, 3H), 1.02-0.91 (m, 5H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation of 2-5 and 2-6.

A mixture of 2-4 (0.07 g, 0.15 mmol) and 10% Pd/C (20 mg) in EtOAc (10mL) was hydrogenated for 36 h at 50° C. under H₂ (50 psi). The reactionmixture was filtered through a pad of celite and the pad was washed withEtOAc (20 mL×3). The combined filtrates were concentrated. The residuewas purified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=25/1) to give 2-5 (25 mg, 35.7%) and 2-6 (20 mg,28.6%) as white powder. ¹H NMR (2-5): (400 MHz, CDCl3) δ 3.87-3.82 (m,1H), 2.05-1.94 (m, 2H), 1.86-1.58 (m, 6H), 1.56-1.17 (m, 16H), 1.13-0.96(m, 6H), 0.93 (d, J=6.8 Hz, 3H), 0.88 (t, J=6.8 Hz, 3H), 0.86-0.84 (m,1H), 0.83 (s, 3H), 0.67-0.61 (m, 4H). ¹H NMR (2-6): (400 MHz, CDCl3) δ3.83-3.76 (m, 1H), 1.95-1.52 (m, 10H), 1.43-0.98 (m, 22H), 0.89 (s, 3H),0.88-0.82 (m, 6H), 0.59 (s, 3H).

Preparation of 2-14.

To a solution of MAD (91 mmol, freshly prepared) in toluene (200 mL) wasadded dropwise a solution of compound 2-13 (10 g, 30 mmol) in toluene(80 mL) at −78° C. during a period of 1 h under nitrogen. Then thereaction mixture was stirred for 30 min, a solution of EtMgBr (91 mL, 91mmol, 1.0 M THF) was added dropwise at −78° C. The reaction mixture waswarmed to −40° C. and stirred at this temperature for 3 h. TLC(petroleum ether:ethyl acetate=3:1) showed that the starting materialwas consumed completely. The mixture was poured into saturated aqueousNH₄Cl solution (200 mL) and extracted with EtOAc (150 mL×2). Thecombined organic phases were dried over Na₂SO₄, and the solvent wasevaporated to afford crude product, which was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=15:1) to give compound 2-14 (4 g, 40%) as white powder.

Preparation of 2-15.

To a solution of 2-14 (4.0 g, 111 mmol) in THF (200 mL) was addedaqueous HCl solution (35 mL, 1 M) and acetone (35 mL). The reactionmixture was stirred for 20° C. at room temperature. TLC (petroleumether:ethyl acetate=3:1) indicated that the reaction was complete. Thenthe reaction mixture was diluted with EtOAc (200 mL), washed withsaturated aqueous NaHCO₃ solution (200 mL), dried over Na₂SO₄ andevaporated under reduced pressure to give 2-15 (3 g, 88%) as whitesolid.

Preparation of 2-16.

To a solution of Ph₃PEtBr (15.8 g, 42.6 mmol) in dry THF (50 mL) wasadded dropwise a solution of t-BuOK (4.8 g, 42.6 mmol) in dry THF (20mL) under N₂ at 0° C. The mixture was stirred at room temperature for1.5 h. Then a solution of 2-15 (2.7 g, 8.5 mmol) in THF (20 mL) wasadded dropwise and the resulting mixture was stirred at 80° C. for 16 h.TLC (petroleum ether:ethyl acetate=3:1) indicated that the startingmaterial was consumed completely. The reaction was quenched withsaturated aqueous NH₄Cl solution (100 mL) and extracted with EtOAc (30mL×2). The combined organic phases were dried over Na₂SO₄ andconcentrated in vacuum. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=12:1) to give 2-16 (1.8 g, 64%) as white solid.

Preparation of 2-17.

To a solution of compound 2-16 (1.8 g, 5.5 mmol) and methyl propiolate(1.1 g, 13.7 mmol) in dry CH₂Cl₂ (20 mL) was added dropwise a solutionof Et₂AlCl (22 mL, 22 mmol, 1 M in toluene) with stirring at 0° C. Thenthe reaction was warmed to room temperature and stirred for 20 h. TLC(petroleum ether:ethyl acetate=5:1) indicated that the starting materialwas consumed completely. The mixture was quenched with saturated aqueousNaHCO₃ solution (30 mL) and extracted with CH₂Cl₂ (30 mL×2). Thecombined organic phases were dried over Na₂SO₄ and concentrated invacuum. The residue was purified by column chromatography on silica gel(eluent: petroleum ether:ethyl acetate=10:1) to give 2-17 (2.0 g, 88%)as white powder. ¹H NMR: (300 MHz, CDCl3) δ 6.99-6.92 (m, 1H) 5.84 (d,J=10.5 Hz, 1H), 5.45-5.41 (m, 1H), 5.32 (d, J=5.2 Hz, 1H), 3.75 (s, 3H),3.06-2.99 (m, 1H), 2.38 (d, J=12.6 Hz, 1H), 2.14-1.67 (m, 10H),1.54-1.25 (m, 7H), 1.21 (d, J=6.8 Hz, 3H), 1.15-0.99 (m, 5H), 0.87 (t,J=7.2 Hz, 3H), 0.80 (s, 3H).

Preparation of 2-18.

To a solution of compound 2-17 (2.2 g, 5.3 mmol) in dry THF (20 mL),DIBAL-H (1 M in THF, 27 mL, 27.0 mmol) was added dropwise at −78° C.under nitrogen. The reaction mixture was warmed to 30° C. and thenstirred for 2 h at 30° C. The reaction was quenched with addition ofwater (3 mL), diluted with EtOAc (200 mL) and dried over anhydrousNa₂SO₄, filtered through a pad of celite and the pad was washed withEtOAc (50 mL×3). The combined filtrates were concentrated in vacuum togive 1.9 g of the crude product, which was directly used in the nextstep without further purification. A mixture of the crude product (1.9g, 4.9 mmol) and MnO₂ (8.6 g, 98 mmol) in CH₂Cl₂ (50 mL) was stirred atroom temperature for 20 h. The reaction mixture was filtered through apad of celite and the pad was washed with CH₂Cl₂ (50 mL×3). The combinedfiltrates were concentrated. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=15:1) to give 2-18 (1.5 g, 79%) as white solid. ¹H NMR: (400MHz, CDCl3) δ 9.55-9.53 (m, 1H), 6.84-6.78 (m, 1H), 6.15-6.09 (m, 1H),5.45-5.41 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 3.15-3.14 (m, 1H), 2.36 (d,J=13.2 Hz, 1H), 2.10-2.03 (m, 3H), 1.90-1.60 (m, 9H), 1.59-1.27 (m, 7H),1.24 (d, J=6.8 Hz, 3H), 1.10-1.22 (m, 6H), 0.87-0.83 (m, 4H), 0.80 (s,3H).

Preparation of 2-19.

To a suspension of 2-18 (1.5 g, 3.92 mmol) and CsF (0.3 g, 1.96 mmol) intoluene/THF (22 mL, 9/1) was added TMSCF₃ (5.8 mL, 39.2 mmol) and themixture was stirred for 20 h at room temperature under nitrogen. TLC(petroleum ether:ethyl acetate=3/1) showed the starting material wasconsumed completely. A solution of TBAF (39.2 mL, 39.2 mmol, 1 M in THF)was added and the mixture was stirred for 4 h at room temperature. Themixture was diluted with MTBE (200 mL), washed with a saturated NaHCO₃solution (30 mL×3) and concentrated in vacuum. The residue was purifiedby column chromatography on silica gel (eluent: petroleum ether:ethylacetate=25/1) to afford 2-19 (0.65 g, 37%) as white solid.

Preparation of 2-20 & 2-21.

2-20 (210 mg, 32%) and 2-21 (210 mg, 32%) were obtained by SFCpurification from 2-19 (650 mg, 1.44 mmol). The configuration of 2-20and 2-21 was confirmed by Mosher method. ¹H NMR (2-20): (400 MHz, CDCl3)δ 5.92 (dd, J₁=15.6 Hz, 0.1=7.2 Hz, 1H), 5.53 (dd, J₁=15.6 Hz, J₂=7.2Hz, 1H), 5.40-5.37 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 4.43-4.40 (m, 1H),2.95-2.94 (m, 1H), 2.37 (d, J=13.6 Hz, 1H), 2.09-1.98 (m, 4H), 1.87-1.18(m, 18H), 1.16 (d, J=6.8 Hz, 3H), 1.12-0.97 (m, 6H), 0.85 (t, J=6.8 Hz,3H), 0.78 (s, 3H). ¹H NMR (2-21): (400 MHz, CDCl3) δ 5.95 (dd, J₁=15.6Hz, J₂=7.2 Hz, 1H), 5.53 (dd, J₁=15.6 Hz, J₂=6.8 Hz, 1H), 5.39-5.36 (m,1H), 5.30 (d, J=5.2 Hz, 1H), 4.44-4.41 (m, 1H), 2.99-2.92 (m, 1H), 2.37(d, J=13.2 Hz, 1H), 2.10-1.98 (m, 4H), 1.87-1.25 (m, 18H), 1.16 (d,J=6.8 Hz, 3H), 1.09-0.99 (m, 6H), 0.85 (t, J=7.2 Hz, 3H), 0.80 (s, 3H).

Preparation of 2-7.

A mixture of 2-20 (200 mg, 0.44 mmol) and 5% Pd/C (50 mg) in EtOAc (20mL) was hydrogenated for 72 h at 30° C. under H₂ (1 atm). The reactionmixture was filtered through a pad of celite and the pad was washed withEtOAc (10 mL×3). The combined filtrates were concentrated. The residuewas purified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=25/1) to afford crude 2-7, which was purified bypre-HPLC to afford 2-7 (64 mg, 52%) as white powder. ¹H NMR (2-7): (400MHz, CDCl3) 5.29 (d, J=4.8 Hz, 1H), 3.90-3.80 (m, 1H), 2.36 (d, J=13.6Hz, 1H), 2.05-1.60 (m, 11H), 1.53-1.06 (m, 15H), 1.03 (s, 3H), 1.02-0.89(m, 5H), 0.85 (t, J₁=14.8 Hz, J₂=7.2 Hz, 3H), 0.69 (s, 3H).

Preparation of 2-8.

A mixture of 2-21 (200 mg, 0.44 mmol) and 5% Pd/C (50 mg) in EtOAc (20mL) was hydrogenated for 72 h at 30° C. under H₂ (1 atm). The reactionmixture was filtered through a pad of celite and the pad was washed withEtOAc (10 mL×3).

The combined filtrates were concentrated. The residue was purified bycolumn chromatography on silica gel (eluent: petroleum ether:ethylacetate=25/1) to afford 2-8 (105 mg, 52%) as white powder. ¹H NMR: (400MHz, CDCl₃) δ 5.29 (d, J=4.8 Hz, 1H), 3.86-3.83 (m, 1H), 2.36 (d, J=13.2Hz, 1H), 2.05-1.95 (m, 4H), 1.86-1.60 (m, 7H), 1.54-1.08 (m, 15H), 1.03(s, 3H), 1.01-0.90 (m, 5H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation of 2-10 and 2-12.

A mixture of 2-8 (30 mg, 0.067 mmol) and 10% Pd/C (10 mg) in EtOAc (10mL) was hydrogenated for 20 h at 50° C. under H₂ (50 psi). The reactionmixture was filtered through a pad of celite and the pad was washed withEtOAc (20 mL×3). The combined filtrates were concentrated. The residuewas purified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=25/1) to give 2-10 (11 mg, 37%) and 2-12 (7 mg, 23%)as white powder. ¹H NMR (2-10): (400 MHz, CDCl3) δ 3.85-3.82 (m, 1H),2.04-1.93 (m, 2H), 1.84-1.59 (m, 6H), 1.56-1.20 (m, 14H), 1.14-0.96 (m,7H), 0.93 (d, J=6.8 Hz, 3H), 0.88-0.84 (m, 4H), 0.83 (s, 3H) 0.67-0.61(m, 4H). 1H NMR (2-12): (400 MHz, CDCl3) δ 3.89-3.80 (m, 1H), 2.08-1.93(m, 2H), 1.91-1.66 (m, 6H), 1.52-1.01 (m, 23H), 0.97 (s, 3H), 0.95-0.90(m, 6H), 0.66 (s, 3H).

Example 3

Preparation of 3-2.

To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) intoluene/THF (20 mL, 8/1) was added TMSCF₃ (1.53 mL, 10.35 mmol) and themixture was stirred for 20° C. at room temperature under nitrogen. TLC(petroleum ether:ethyl acetate=3/1) showed the starting material wasconsumed completely. A solution of TBAF (6.8 mL, 1 M in THF) was addedand the mixture was stirred for 4 h at room temperature. The mixture wasdiluted with MTBE (200 mL), washed with aq. saturated NaHCO₃ solution(30 mL×3) and concentrated in vacuum. The residue was purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=20:1) to afford 3-2 (220 mg, 46%) as white solid. ¹H NMR: (400MHz, CDCl3) δ 5.31 (d, J=2.0 Hz, 1H), 2.44-2.41 (m, 1H), 2.04-1.96 (m,3H), 1.81-1.67 (m, 5H), 1.65-1.39 (m, 11H), 1.34-1.32 (m, 3H), 1.31-1.25(m, 1H), 1.21-1.10 (m, 3H), 1.12-0.98 (m, 4H), 0.96 (s, 3H), 0.98-0.90(m, 4H), 0.68 (s, 3H.)

Preparation of 3-3 and 3-4.

To a solution of compound 3-2 (220 mg, 0.569 mmol) in EtOAc (10 mL) wasadded Pd/C (20 mg), then the mixture was stirred under hydrogen (50 psi)at 50° C. overnight. The mixture was filtered through a pad of celiteand the filtrate was evaporated under reduced pressure. The residue waspurified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=20:1) to afford the pure product 3-3 (100 mg, 38.5%)and 3-4 (51 mg, 19.3%) as white powder. ¹H NMR (3-3): (400 MHz, CDCl3) δ2.01-1.95 (m, 1H), 1.89-1.75 (m, 2H), 1.69-1.55 (m, 9H), 1.52-1.43 (m,5H), 1.32-1.28 (m, 4H), 1.27-1.20 (m, 7H), 1.17-1.08 (m, 4H), 1.06-0.96(m, 3H), 0.96-0.91 (m, 3H), 0.80 (s, 3H), 0.68-0.49 (m, 4H). ¹H NMR(3-4): (400 MHz, CDCl3) δ 2.01-1.95 (m, 1H), 1.89-1.67 (m, 5H),1.66-1.60 (m, 2H), 1.63-1.36 (m, 8H), 1.35-1.31 (m, 4H), 1.29-1.24 (m,4H), 1.22 (s, 3H), 1.28-1.06 (m, 6H), 0.96 (s, 3H), 0.95-0.92 (m, 3H),0.68 (s, 3H).

Preparation of 3-5 and 3-6.

Compound 3-2 (1.2 g, 2.63 mmol) was split by SFC to get Product 3-5 (400mg) and 3-6(400 mg) as white powder (total yield: 66.7%). ¹H NMR (3-5):(400 MHz, CDCl₃) δ 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40 (m, 1H), 2.08-1.95(m, 3H), 1.90-0.90 (m, 35H), 0.70 (s, 3H). ¹H NMR (3-6): (400 MHz,CDCl₃) δ 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40 (m, 1H), 2.08-1.95 (m, 3H),1.90-0.92 (m, 35H), 0.70 (s, 3H).

Preparation of 3-7

To a solution of compound 3-6 (300 mg, 0.66 mmol) in EtOAc (8 mL) wasadded Pd/C (10%, 200 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. Then the mixture was stirredunder H₂ (50 psi) at 50° C. for 24 h. The suspension was filteredthrough a pad of celite and the pad was washed with EtOAc (50 mL×2). Thecombined filtrates were concentrated to dryness to give the crudeproduct, which was purified by column chromatography on silica gel(petroleum ether:ethyl acetate=20:1) to afford 3-7 (142 mg, 47%) aswhite solid. ¹H NMR: (3-7) (400 MHz, CDCl₃) δ 1.96-1.92 (m, 1H),1.90-1.75 (m, 1H), 1.70-1.57 (m, 5H), 1.55-1.35 (m, 6H), 1.30-1.20 (m,12H), 1.20-1.06 (m, 12H), 1.19-0.81 (m, 1H), 0.80 (s, 3H), 0.70-0.60 (m,4H). ¹H NMR: (3-7A) (400 MHz, CDCl₃) δ 1.96-1.92 (m, 1H), 1.90-1.75 (m,3H), 1.70-1.57 (m, 2H), 1.55-1.25 (m, 13H), 1.21-1.00 (m, 15H),0.96-0.86 (m, 8H), 0.65 (s, 3H)

Preparation of 3-8

To a solution of compound 3-5 (300 mg, 0.66 mmol) in EtOAc (8 mL) wasadded Pd/C (10%, 200 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. Then the mixture was stirredunder H₂ (50 psi) at 50° C. for 24 h. The suspension was filteredthrough a pad of celite and the pad was washed with EtOAc (50 mL×2). Thecombined filtrates were concentrated to dryness to give the crudeproduct, which was purified by column chromatography on silica gel(petroleum ether:ethyl acetate=20:1) to afford 3-8 (141.6 mg, 47%) aswhite solid. ¹H NMR: (3-8) (400 MHz, CDCl₃) δ 1.96-1.92 (m, 1H),1.90-1.70 (m, 2H), 1.69-1.57 (m, 5H), 1.55-1.20 (m, 18H), 1.19-0.81 (m,10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). ¹H NMR: (3-8A) (400 MHz, CDCl₃) δ1.97-1.70 (m, 6H), 1.70-1.57 (m, 2H), 1.50-1.30 (m, 13H), 1.25-1.05 (m,15H), 1.00-0.86 (m, 7H), 0.65 (s, 3H)

Example 4

Preparation of Compound 4-2.

To a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL) at roomtemperature was added HATU (46.3 g, 121.8 mmol), DIPEA (45.9 g, 355.2mmol). The mixture was stirred for 1 h, and N,O-dimethylhydroxylaminehydrochloride (19.8 g, 203 mmol) was added. The mixture was stirred atroom temperature for another 6 h. The reaction mixture was concentrated,poured into water, extracted with EtOAc, washed with water, dried overNa₂SO₄, and concentrated to give crude product. The crude product waspurified by column chromatography on silica gel (eluent: PE:EA=3:1) toafford the desired product 4-2 (24 g, 57%) as white solid. ¹H NMR: (300MHz, CDCl3) δ: ppm 5.25 (d, J=5.2 Hz, 1H), 3.59 (s, 3H), 3.46-3.37 (m,1H), 3.07 (s, 3H), 2.70 (s, 1H), 2.40-2.09 (m, 4H), 1.92-1.63 (m, 6H),1.44-1.33 (m, 6H), 1.29-1.15 (m, 3H), 1.11-0.93 (m, 5H), 0.90 (s, 3H),0.85 (d, J=6.4 Hz, 3H), 0.82-0.78 (m, 1H), 0.58 (s, 3H).

Preparation of Compound 4-3.

To a solution of compound 4-2 (14 g, 33.52 mmol, 1.0 eq) in dry CH₂Cl₂(600 mL) was added Dess-Martin (28 g, 67.04 mmol, 2.0 eq) in portions at0° C. Then the reaction mixture was stirred at room temperature for 6.5h. TLC (PE: EA=3:1) showed the starting material was consumedcompletely. The mixture was quenched with saturated aqueousNaHCO₃/Na₂S₂O₃=1:3 (800 mL). The organic phase was washed with brine(500 mL) and dried over Na₂SO₄, and the solvent was evaporated to affordcrude product 4-3 (14.0 g, 100%), which was directly used in the nextstep without further purification.

Preparation of Compound 4-4.

To a solution of MAD (101 mmol, 3.0 eq) in toluene, freshly prepared byaddition of a solution of Me₃Al (50.5 mL, 101.00 mmol, 2 M in hexane) toa stirred solution of 2,6-di-tert-butyl-4-methylphenol (44.4 g, 202mmol) in toluene (200 mL) followed by stirring for 1 h at roomtemperature, was added dropwise a solution of 4-3 (14.0 g, 33.7 mmol,1.0 eq) in toluene (10 mL) at −78° C. under nitrogen. Then the reactionmixture was stirred for 30 min, a solution of MeMgBr (33.7 mL, 101 mmol,3.0 eq, 3 M in ether) was added dropwise at −78° C. The reaction mixturewas warmed to 25° C. and stirred at this temperature for 12 h. TLC(PE:EA=3:1) showed that the starting material was consumed completely.The mixture was poured into aqueous saturated NH₄Cl solution (200 mL)and extracted with EtOAc (200 mL×2). The combined organic phases weredried over Na₂SO₄, and the solvent was evaporated to afford crudeproduct. The crude product was purified by column chromatography onsilica gel (eluent: PE:EA=3:1) to give the pure target (7.5 g, 52%) aswhite powder. ¹H NMR: (400 MHz, CDCl3) 5.30 (d, J=5.2 Hz, 1H), 3.69 (s,3H), 3.17 (s, 3H), 2.50-2.30 (m, 3H), 2.05-1.70 (m, 7H), 1.52-1.30 (m,9H), 1.20-0.90 (m, 15H), 0.68 (s, 3H).

Preparation of Compound 4-5.

To a solution of compound 4-4 (7.5 g, 17.4 mmol, 1.0 eq) in THF (150 mL)was added dropwise a solution of MeMgBr (29 mL, 87 mmol, 5.0 eq, 3 M inTHF) at room temperature during a period of 30 min under nitrogen. Thenthe reaction mixture was stirred at room temperature for 12 h. TLC(PE:EA=1:1) showed that the starting material was consumed completely.The mixture was poured into aqueous saturated NH₄Cl solution (200 mL)and extracted with EtOAc (150 mL×2). The combined organic phases weredried over Na₂SO₄, and the solvent was evaporated to afford crudeproduct. The crude product was purified by column chromatography onsilica gel (eluent: PE:EA=4:1) to give the product 4-5 (5.2 g, 77%) aswhite powder. ¹H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H),2.50-2.30 (m, 3H), 2.14 (s, 3H) 2.03-1.93 (m, 3H), 1.87-1.68 (m, 4H),1.60-1.18 (m, 12H), 1.12 (s, 3H), 1.11-1.03 (m, 1H), 1.01 (s, 3H),1.00-0.94 (m, 1H), 0.91 (d, J=6.4 Hz, 3H), 0.68 (s, 3H).

Preparation of 4-6.

To a solution of compound 4-5 (300 mg, 0.777 mmol, 1.0 eq) in toluene (5mL) was added dropwise a solution of EtMgBr (4.5 mL, 4.5 mmol, 6.0 eq, 1M in THF) at room temperature during a period of 10 min under nitrogen.Then the reaction mixture was stirred at room temperature for 12 h. TLC(PE:EA=3:1) showed that the starting material was consumed completely.The mixture was poured into aqueous saturated NH₄Cl solution (20 mL) andextracted with EtOAc (50 mL×2). The combined organic phases were driedover Na₂SO₄, and the solvent was evaporated to afford crude product. Thecrude product purified by column chromatography on silica gel (eluent:PE:EA=8:1) to give the product 4-6 (200 mg, 62%) as white powder. ¹HNMR: (400 MHz, CDCl3) δ 5.23 (d, J=5.6 Hz, 1H), 2.40-2.30 (m, 1H),2.00-1.55 (m, 7H), 1.50-1.98 (m, 25H), 0.95 (s, 3H), 0.94-0.80 (m, 8H),0.62 (s, 3H).

Preparation of 4-7 and 4-8.

To a solution of compound 4-6 (175 mg, 0.42 mmol) in EtOAc (10 mL) wasadded 10% Pd/C (40 mg) under argon. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (50 Psi) at 50° C. overnight. The suspension was filtered through apad of celite and the pad was washed with EA (20 mL×3). The combinedfiltrates were concentrated in vacuum and the residue was purified bycolumn chromatography on silica gel (eluent: PE:EA=8:1) to give 4-7 (84mg, 48%) and 4-8 (25 mg, 14%) as white powder. ¹H NMR (4-7): (400 MHz,CDCl3) δ 1.98-1.92 (m, 1H), 1.87-1.78 (m, 1H), 1.70-1.60 (m, 2H),1.58-1.20 (m, 21H), 1.20-0.97 (m, 11H), 0.95-0.82 (m, 7H), 0.80 (s, 3H),0.70-0.61 (m, 4H). ¹H NMR (4-8): (400 MHz, CDCl3) δ 2.00-1.78 (m, 4H),1.68-1.63 (m, 1H), 1.57-1.55 (m, 1H), 1.53-1.35 (m, 10H), 1.32-1.12 (m,16H), 1.11-0.99 (m, 5H), 0.97 (s, 3H), 0.95-0.83 (m, 6H), 0.67 (s, 3H).

Preparation of 4-9

To a solution of compound 10-12B (80 mg, 0.193 mmol) in EtOAc (20 mL)was added 10% Pd/C (20 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. Then the mixture was stirredunder H₂ (50 psi) at 50° C. for 12 hours. The mixture was filteredthrough a pad of celite and the pad was washed with EtOAc (5 mL×2). Thecombined filtrates were concentrated to dryness to give the product,which was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=12:1 to 10:1) to afford the 4-9 (40 mg,50%) as white powder. ¹H NMR (4-9): (400 MHz, CDCl₃) δ 2.02-1.93 (m,1H), 1.92-1.80 (m, 1H), 1.70-0.85 (m, 41H), 0.82 (s, 3H), 0.67 (s, 3H).

Preparation of 4-10

To a solution of compound 10-12A (80 mg, 0.193 mmol) in EtOAc (20 mL)was added 10% Pd/C (20 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. Then the mixture was stirredunder H₂ (50 psi) at 50° C. for 48 hours. The mixture was filteredthrough a pad of celite and the pad was washed with EtOAc (5 mL×2). Thecombined filtrates were concentrated to dryness to give the product,which was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=12:1 to 10:1) to afford the 4-10 (40 mg,50%) as white powder. ¹H NMR (4-10): (400 MHz, CDCl₃) δ 2.02-1.93 (m,1H), 1.92-1.80 (m, 1H), 1.70-0.85 (m, 41H), 0.82 (s, 3H), 0.67 (s, 3H).

Preparation of 4-11 and 4-12.

4-11 (100 mg, 15.38%) and 4-12 (90 mg, 13.85%) were obtained by SFCpurification from 4-6 (600 mg, 1.55 mmol). ¹H NMR (Isomer 1): (400 MHz,CDCl3) δ 5.30 (m, 1H), 2.43-2.40 (d, J=12.4 Hz, 1H), 2.14-1.99 (m, 3H),1.96-1.68 (m, 3H), 1.68-1.52 (m, 5H), 1.51-1.24 (m, 13H), 1.19-1.09 (m,8H), 1.02 (s, 3H), 0.96-0.93 (m, 3H), 0.93-0.87 (m, 3H), 0.69 (s, 3H).¹H NMR (Isomer 2): (400 MHz, CDCl3) δ 5.30 (m, 1H), 2.44-2.40 (d, J=14Hz, 1H), 2.17-1.96 (m, 3H), 1.96-1.67 (m, 3H), 1.67-1.18 (m, 18H),1.16-1.09 (m, 8H), 1.06 (s, 3H), 0.96-0.93 (m, 3H), 0.93-0.87 (m, 3H),0.69 (s, 3H).

Example 5

Preparation of Compound 5-2.

To a solution of 5-1 (200 mg, 0.52 mmol) in toluene (5 mL) at −78° C.was added n-PrMgBr (1.3 mL, 2 M in THF, 2.6 mmol) dropwise. The mixturewas warmed up to room temperature gradually and stirred for 6 h. Thereaction mixture was quenched with NH₄Cl aqueous, extracted with EtOAc.The organic layer was dried over Na₂SO₄, and concentrated to give crudeproduct. The crude product was purified by column chromatography onsilica gel (eluent: PE:EA=15:1) to afford 5-2 (130 mg, 58%) as whitesolid. ¹H NMR: (300 MHz, CDCl3) δ: ppm 5.30 (d, J=4.8 Hz, 1H), 2.48-2.38(m, 1H), 2.02-1.95 (m, 3H), 1.88-1.66 (m, 3H), 1.63-1.52 (m, 5H),1.52-1.46 (m, 4H), 1.43-1.41 (m, 1H), 1.41-1.35 (m, 4H), 1.30-1.22 (m,3H), 1.20-1.14 (m, 4H), 1.13-1.08 (m, 4H), 1.03 (s, 3H), 0.95-0.90 (m,3H), 0.90-0.87 (m, 3H), 0.87-0.85 (m, 1H) 0.68 (s, 3H).

Preparation of 5-3and 5-4.

To a solution of compound 5-2 (400 mg, 0.93 mmol) in EtOAc (20 mL) wasadded 10% Pd/C (100 mg). Then the mixture was stirred under hydrogen (50psi) at 50° C. overnight. The mixture was filtered through a pad ofcelite and the filtrate was evaporated under reduced pressure. Theresidue was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=15:1) to afford the pure product 5-3(150mg, 37.3%) and 5-4 (27 mg, 6.7%) as white powder. ¹H NMR (5-3): (300MHz, CDCl3) δ 1.97-1.94 (m, 1H), 1.93-1.77 (m, 1H), 1.67-1.62 (m, 3H),1.56-1.51 (m, 6H), 1.47-1.30 (m, 11H), 1.24 (s, 6H), 1.20 (s, 1H), 1.13(s, 5H), 1.09-0.99 (m, 4H), 0.94-0.90 (m, 6H), 0.80 (s, 3H), 0.65 (s,3H). ¹H NMR (5-4): (300 MHz, CDCl3) δ 1.98-1.94 (m, 2H), 1.91-1.78 (m,5H), 1.65-1.51 (m, 5H), 1.47-1.46 (m, 3H), 1.38-1.35 (m, 9H), 1.32-1.30(m, 2H), 1.25 (s, 3H), 1.22 (s, 6H), 1.16-1.10 (m, 4H), 1.06-1.04 (m,4H), 0.98-0.94 (m, 4H), 0.92-0.89 (m, 6H), 0.86-0.83 (m, 1H), 0.64 (s,3H).

Preparation of 5-5 and 5-6

To a solution of compound 5-1 (1500 mg, 3.88 mmol) in dry THF (30 mL)was added a solution of n-PrMgBr (11.6 mL, 23.3 mmol) dropwise at 0° C.The mixture was stirred at 40° C. for 16 h. TLC (PE/EtOAc=2/1) showedthe reaction was complete. Saturated aqueous NH₄Cl (5 mL) was addedslowly to quench the reaction. The resulting solution was separatedbetween EtOAc (30 mL×3) and H₂O (30 mL). The combined organic layerswere concentrated in vacuum and the residue was purified by silica gelcolumn eluted with PE/EtOAc=10/1 to give the mixture of thediastereomeric pair (1.1 g) as white power. The diastereomeric pair wasseparated by prep-SFC to give 5-6 (380 mg, 22.8%) as a white solid and5-5 (385 mg, 23.1%) as a white solid. ¹H NMR (5-5): (400 MHz, CDCl₃)5.31-5.30 (m, 1H), 2.44-2.41 (d, 1H, J=12.8 Hz), 2.01-1.96 (m, 3H),1.86-1.69 (m, 3H), 1.58-1.25 (m, 16H), 1.14-1.08 (m, 11H), 1.06-0.99 (m,4H), 0.94-0.91 (m, 6H), 0.68 (s, 3H). ¹H NMR (5-6): (400 MHz, CDCl₃) δ5.31-5.30 (m, 1H,), 2.44-2.41 (d, 1H, J=12.4 Hz), 2.02-1.96 (m, 3H),1.87-1.68 (m, 3H), 1.57-1.25 (m, 16H), 1.18-1.08 (m, 10H), 1.02-0.99 (m,4H), 0.94-0.91 (m, 6H), 0.68 (s, 3H).

Preparation of 5-8

A mixture of 5-6 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAc(30 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50° C. Thereaction mixture was filtered through a celite pad. The pad was washedwith EtOAc (50 mL). The filtrate was concentrated in vacuum and theresidue was purified by silica gel column eluted with PE/EtOAc=20/1 togive 5-8 (111.3 mg, 55.4%) as a white solid. ¹H NMR (5-8) (400 MHz,CDCl₃), δ (ppm) 1.97-1.94 (d, 1H, J=12.0 Hz), 1.83-1.78 (m, 1H),1.65-1.61 (m, 3H), 1.50-1.24 (m, 20H), 1.13-1.00 (m, 11H), 0.94-0.85 (m,7H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). ¹H NMR (5-8A) (400 MHz, CDCl₃), δ(ppm) 1.98-1.95 (d, 1H, J=11.2 Hz), 1.88-1.80 (m, 3H), 1.65-1.60 (m,1H), 1.51-1.47 (m, 1H), 1.40-1.31 (m, 12H), 1.28-1.20 (m, 8H), 1.16-1.01(m, 11H), 0.96-0.80 (m, 10H), 0.65 (s, 3H).

Preparation of 5-7

A mixture of 5-5 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAc(30 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50° C. Thereaction mixture was filtered through a celite pad. The pad was washedwith EtOAc (50 mL). The filtrate was concentrated in vacuum and theresidue was purified by silica gel column eluted with PE/EtOAc=20/1 togive 5-7 (118.5 mg, 59.0%) as a white solid. ¹H NMR (5-7) (400 MHz,CDCl₃), δ (ppm) 1.97-1.94 (d, 1H, J=12.8 Hz), 1.88-1.79 (m, 1H),1.71-1.61 (m, 3H), 1.51-1.24 (m, 20H), 1.13-1.00 (m, 11H), 0.94-0.85 (m,7H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). ¹H NMR (5-7A) (400 MHz, CDCl₃), δ(ppm) 1.98-1.95 (d, 1H, J=1.2 Hz), 1.88-1.79 (m, 3H), 1.65-1.59 (m, 1H),1.52-1.47 (m, 1H), 1.41-1.31 (m, 1H), 1.27-1.22 (m, 9H), 1.13-1.11 (m,7H), 1.06-1.01 (m, 4H), 0.96-0.90 (m, 10H), 0.65 (s, 3H).

Example 6

Preparation of 6-2.

To a solution of 6-1 (150 mg, 0.39 mmole) in THF (4 mL) was addedallylmagnesium bromide (2.34 mL, 2.34 mmole, 1M in ether) at −78° C.Then the reaction mixture was warmed to room temperature and stirred for12 hours. The mixture was quenched with NH₄Cl (20 mL) solution andextracted with EtOAc (10 mL×2). The organic phase was dried by Na₂SO₄and purified by column chromatography on silica gel (eluent: PE:EA=10:1) to get the 6-2 (100 mg, 59%). ¹H NMR: (400 MHz, CDCl₃) δ5.89-5.82 (m, 1H), 5.31 (d, J=5.2 Hz, 2H), 5.15-5.09 (m, 2H), 2.43-2.40(m, 1H), 2.22-2.20 (d, J=7.6 Hz, 2H), 2.04-1.96 (m, 3H), 1.95-1.57 (m,3H), 1.54-1.24 (m, 12H), 1.19-1.11 (m, 5H), 1.09-1.05 (m, 6H), 1.03 (s,3H), 0.98-0.92 (m, 5H), 0.68 (s, 3H).

Preparation of 6-3.

To a solution of 9-BBN (3.2 mL, 1.6 mmol, 2M in THF) was added dropwisea solution of 6-2 (70 mg, 0.16 mmol) in THF (2 mL) at 0° C. The reactionmixture was heated at 60° C. and stirred for 12 hours. The mixture wascooled to 0° C. and aq. NaOH (10%) solution (2 mL) was added followed byH₂O₂ (30%, 1 mL). The mixture was stirred for 2 hours at 0° C. and thenextracted with EtOAc. The combined organic layer was washed with brine,dried over Na₂SO₄ and concentrated to give crude product. The crudeproduct was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=2:1) to afford 6-3 (30 mg, 42%) as whitesolid. ¹H NMR: (300 MHz, CDCl3) δ: 5.30 (d, J=5.2 Hz, 1H), 3.68-3.65 (m,2H), 2.43-2.39 (m, 1H), 2.03-1.80 (m, 6H), 1.79-1.62 (m, 6H), 1.47-1.36(m, 5H), 1.32-1.25 (m, 7H), 1.17-1.13 (m, 4H), 1.11-1.07 (m, 6H),10.5-0.98 (m, 4H), 0.94-0.90 (m, 5H), 0.68 (s, 3H).

Preparation of 6-4 and 6-5.

A mixture of 6-1 (1.0 g, 2.59 mmol) and 10% Pd/C (140 mg) in EtOAc (30mL) was hydrogenated for 16 h at 50° C. under H₂ (50 psi). The reactionmixture was filtered through a pad of celite and the pad was washed withEtOAc (20 mL×3). The combined filtrates were concentrated. The residuewas purified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=15:1) to afford 6-4 (500 mg, 49.5%) and 6-5 (200 mg,19.8%) as white solid.

Preparation of 6-6.

To a solution of 6-4 (70 mg, 0.18 mmol) in dry THF (2 mL) at −78 OC wasadded C₃H₅MgBr (1.1 mL, 1.08 mmol) dropwise under N₂. The mixture waswarmed up to room temperature gradually and stirred for 12 h. Thereaction was quenched with NH₄Cl aqueous and extracted by EtOAc. Theorganic layer was dried over Na₂SO₄, filtered and concentrated to givecrude product. The crude product was purified by column chromatographyon silica gel (eluent: petroleum ether:ethyl acetate=15:1) to afford thepure product 6-6 (40 mg, 51.9%) as white powder. ¹H NMR: (300 MHz,CDCl3) δ: ppm 5.92-5.79 (m, 1H), 5.15 (d, J=4.2 Hz, 1H), 5.11 (d, J=13.2Hz, 1H), 2.21 (d, J=7.5 Hz, 2H), 1.97-1.75 (m, 5H), 1.67-1.34 (m, 19H),1.30-0.94 (m, 11H), 0.91 (d, J=6.3 Hz, 3H), 0.80 (s, 3H), 0.69-0.61 (m,4H).

Preparation of 6-7 and 6-8

Compound 6-2 (400 mg, 0.849 mmol) was split by SFC to get 6-7 (96 mg)and 6-8 (162 mg) as white powder (total yield: 650%/). ¹H NMR (6-7) (400MHz, CDCl₃), δ 5.90-5.81 (m, 1H), 5.31 (d, J=5.2 Hz, 1H), 5.20-5.09 (m,2H), 2.45-2.35 (m, 1H), 2.25-2.15 (m, 2H), 2.04-0.90 (m, 36H), 0.68 (s,3H). ¹H NMR (6-8) (400 MHz, CDCl₃), δ 5.90-5.80 (m, 1H), 5.31 (d, J=5.2Hz, 1H), 5.21-5.09 (m, 2H), 2.45-2.34 (m, 1H), 2.25-2.15 (m, 2H),2.04-0.89 (m, 36H), 0.68 (s, 3H).

Preparation of 6-6-Bz

To a solution of 6-6 (100 mg, 0.23 mmol) in pyridine (3 mL) was addedBzCl (64.4 mg, 0.46 mmol) dropwise at room temperature. Then thereaction mixture was stirred at 40° C. for 12 hours. TLC showed thestarting material was consumed completely. The mixture was quenched bysaturated aqueous water and extracted with EtOAc. The combined organicphase was washed with 1 M HCl (30 mL) and brine, dried over anhydrousNa₂SO₄ then concentrated in vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=80:1) toafford 6-8-Bz (60 mg, 48%) as a white solid.

Preparation of 6-11-Bz

Compound 6-6-Bz (60 mg, 0.11 mmol) was split by SFC to get 6-11-Bz (40mg, 66%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ 7.99-7.98 (d,J=7.2 Hz, 2H), 7.53-7.49 (t, J=7.2 Hz, 1H), 7.42-7.38 (t, J=7.2 Hz, 2H),2.22-2.20 (d, J=7.6 Hz, 2H), 1.98-1.57 (m, 11H), 1.54-1.26 (m, 16H),1.15 (s, 3H), 1.12-1.10 (m, 6H), 0.92-0.91 (d, J=6.0 Hz, 3H), 0.80 (s,3H), 0.64-0.60 (m, 4H)

Preparation of 6-11

To a solution of compound 6-11-Bz (40 mg, 0.075 mmol) in a mixturesolvent of THF (2 mL) and MeOH (1 mL) was added a solution of LiOH (90mg, 3.75 mmol) in H₂O (1 mL). The mixture was stirred at 40° C. for 3days. TLC showed the starting material was consumed completely. Thereaction mixture was treated with water and extracted with EtOAc. Thecombined organic phase was washed with brine, dried over anhydrousNa₂SO₄ then concentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=8:1) toafford 6-11 (23 mg, 71%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ5.86-5.84 (m, 1H), 5.13-5.09 (m, 2H), 2.21-2.19 (d, J=7.6 Hz, 2H),1.84-1.25 (m, 19H), 1.24 (s, 3H), 1.14 (s, 3H), 1.13-1.09 (m, 7H),0.91-0.90 (d, J=6.8 Hz, 3H), 0.80 (s, 3H), 0.64-0.60 (m, 4H)

Example 7

Preparation of Compound 7-2.

To a solution of 7-1 (193 mg, 0.5 mmol, 1.0 eq) in dry THF (3 mL),n-BuLi (1.6 mL, 4 mmol, 8.0 eq) was added dropwise at −78° C. Theresulting mixture was stirred at this temperature for 0.5 h, and thenthe temperature was allowed to warm to room temperature and stirred atthis temperature for another 18 h. TLC (PE/EA=5/1) showed the reactionwas complete. The mixture was quenched with saturated aqueous NH₄Cl andextracted with EtOAc (10 mL×3). The combined organic layers were washedwith brine (10 mL), dried over sodium sulfate and concentrated invacuum. The residue was purified by column chromatography on silica gel(eluent: PE:EA=20:1) to give the product 7-2 (85 mg, 38.6%) as whitepowder. ¹H NMR: (400 MHz, CDCl₃) δ 5.31 (d, J=5.2 Hz, 1H), 2.41 (d,J=13.2 Hz, 1H), 2.10-1.95 (m, 3H), 1.94-1.62 (m, 42H), 1.52-1.22 (m,17H), 1.22-1.20 (m, 1H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H),1.04-1.00 (m, 3H), 1.00-0.85 (m, 9H), 0.67 (s, 3H).

Preparation of Compound 7-3.

A mixture of 7-2 (100 mg, 2.59 mmol) and 10% Pd/C (140 mg) in EtOAc (30mL) was hydrogenated for 16 h at 50° C. under H₂ (50 psi). The reactionmixture was filtered through a pad of celite and the pad was washed withEtOAc (20 mL×3). The combined filtrates were concentrated. The residuewas purified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=15:1) to afford 7-3 (35 mg, 35%) and 7-3A (19 mg,19%) as white powder. ¹H NMR (7-3): (400 MHz, CDCl3) δ 2.02-1.92 (m,1H), 1.90-1.77 (m, 1H), 1.70-1.38 (m, 14H), 1.36-1.29 (m, 6H), 1.28-1.20(m, 8H), 1.20-1.08 (m, 6H), 1.07-0.96 (m, 4H), 0.96-0.84 (m, 7H), 0.82(s, 3H), 0.70-0.60 (m, 4H). ¹H NMR (7-3A): (400 MHz, CDCl3) δ 1.98-1.80(m, 4H), 1.67-1.48 (m, 6H), 1.45-1.33 (m, 9H), 1.32-1.23 (m, 10H),1.22-1.18 (m, 4H), 1.17-1.10 (m, 6H), 1.10-0.97 (m, 4H), 0.94 (s, 3H),0.93-0.87 (m, 6H), 0.64 (s, 3H).

Preparation of 7-4 and 7-5

To a solution of compound 7-1 (1.5 g, 3.88 mmol) in dry THF (15 mL) wasadded n-BuLi (12.5 mL, 31 mmol, 2.5 M in THF) dropwise at −78° C. Theresulting mixture was stirred at this temperature for 0.5 h, and thenthe temperature was allowed to warm to room temperature and stirred atthis temperature for another 18 h. TLC (PE/EA=5/1) showed the reactionwas complete. The mixture was quenched with saturated aqueous NH₄Cl andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (10 mL), dried over sodium sulfate and concentrated invacuum. The residue was purified by column chromatography on silica gel(eluent: PE:EA=20:1) to give 7-2 (800 mg, 46.4%) as white powder, whichwas split by SFC to give 7-4 (207 mg) and 7-5 (360 mg) as white powder.¹H NMR (7-4): (400 MHz, CDCl3) δ 5.38-5.29 (m, 1H), 2.44 (d, 1H, J=12.5Hz), 2.04-1.69 (m, 6H), 1.57-1.25 (m, 18H), 1.20-0.89 (m, 23H), 0.70 (s,3H). ¹H NMR (7-5): (400 MHz, CDCl3) δ 5.32 (s, 1H), 2.44 (d, 1H, J=12.3Hz), 2.08-1.68 (m, 6H), 2.55-1.25 (m, 17H), 2.22-0.85 (m, 24H), 0.70 (s,3H).

Preparation of 7-6

To a solution of 7-4 (0.17 g, 0.38 mmol) in 15 mL EtOH was added Pd/C(100 mg) then the reaction mixture was stirred under hydrogen (50 psi)at 50° C. for 24 h. The resulting solution was filtered andconcentrated. The product was purified by column chromatograph on silicagel elude with (PE:EA=20:1) to give 7-6 (40 mg, yield: 23.42%) as whitesolid. ¹H NMR (7-6) (400 MHz, CDCl₃), δ 1.97-1.94 (m, 1H,), 1.88-1.76(m, 1H), 1.71-1.59 (m, 3H): 1.56-1.23 (m, 21H), 1.23-0.86 (m, 19H), 0.81(s, 3H), 0.65 (s, 3H).

Preparation of 7-7

To a solution of 7-5 (0.23 g, 0.52 mmol) in 15 mL EtOH was added Pd/C(200 mg), then the reaction mixture was stirred under hydrogen (50 psi)at 50° C. for 24 h. The resulting solution was filtered andconcentrated. The product was purified by column chromatograph on silicagel elude with (PE:EA=20:1) to give 7-7 (70 mg, yield: 30.3%) as whitesolid. ¹H NMR (7-7) (400 MHz, CDCl₃), δ (ppm) 1.99-1.92 (m, 1H,),1.88-1.78 (m, 1H), 1.70-1.52 (m, 6H), 1.46-1.20 (m, 21H), 1.18-0.87 (m,20H), 0.81 (s, 3H), 0.65 (s, 3H).

Example 8

Preparation of 8-2.

To a solution of compound 8-1 (100 mg, 0.25 mmol) in toluene (8 mL) wasadded dropwise a solution of i-PrMgBr (1.5 mL, 1.5 mmol, 1 M in THF) atroom temperature during a period of 10 min under nitrogen. Then thereaction mixture was stirred at room temperature for 12 h. TLC showedthat the starting material was consumed completely. The mixture waspoured into aqueous saturated NH₄Cl solution (20 mL) and extracted withEtOAc (50 mL×2). The combined organic phases were dried over Na₂SO₄, andthe solvent was evaporated to afford crude product. The crude productpurified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=8:1) to give the product 8-2 (66 mg, 59.46%) aswhite powder. 1H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H),2.43-2.40 (m, 1H), 2.04-1.55 (m, 3H), 1.88-1.66 (m, 5H), 1.58-1.13 (m,15H), 1.11 (s, 3H), 1.08 (s, 3H), 1.01 (s, 3H), 0.96-0.90 (m, 6H),0.90-0.86 (m, 3H), 0.68 (s, 3H).

Preparation of 8-3 and 8-4.

To a solution of compound 8-2 (60 mg, 0.14 mmol) in EtOAc (15 mL) wasadded 10% Pd/C (20 mg) under argon. The suspension was degassed undervacuum and purged with H₂ several times. The mixture was stirred underH₂ (50 Psi) at 50° C. overnight. The suspension was filtered through apad of celite and the pad was washed with EA (20 mL×3). The combinedfiltrates were concentrated in vacuum and the residue was purified bycolumn chromatography on silica gel (eluent: petroleum ether:ethylacetate=10:1) to give 8-3 (27 mg, 45%) and 8-4 (9 mg, 15%) as whitepowder. ¹H NMR (8-3): (400 MHz, CDCl3) δ 1.97-1.94 (m, 1H), 1.85-1.78(m, 2H), 1.74-1.42 (m, 12H), 1.48-1.20 (m, 12H), 1.18-1.09 (m, 3H), 1.07(s, 3H), 1.02-0.98 (m, 2H), 0.93-0.88 (m, 6H), 0.88-0.86 (m, 3H), 0.80(s, 3H), 0.63 (s, 3H). ¹H NMR (8-4): (400 MHz, CDCl3) δ1.98-1.95 (m,1H), 1.89-1.79 (m, 3H), 1.75-1.54 (m, 7H), 1.48-1.24 (m, 16H), 1.23 (s,3H), 1.19-1.11 (m, 4H), 1.08 (s, 4H), 0.95 (s, 3H), 0.94-0.88 (m, 6H),0.88-0.86 (m, 3H), 0.63 (s, 3H).

Preparation of 8-7and 8-8.

To a solution of compound 8-1 (1500 mg, 3.88 mmol) in dry THF (30 mL)was added a solution of i-PrMgCl (11.6 mL, 23.3 mmol) dropwise at 0° C.The mixture was stirred at 40° C. for 16 h. TLC (PE/EtOAc=2/1) showedthe reaction was complete. Saturated aqueous NH₄Cl (5 mL) was addedslowly to quench the reaction. The resulting solution was separatedbetween EtOAc (30 mL×3) and H₂O (30 mL). The combined organic layerswere concentrated in vacuum and the residue was purified by silica gelcolumn eluted with PE/EtOAc=10/1 to give the mixture of thediastereomeric pair (800 mg) as white power. The diastereomeric pair wasseparated by prep-SFC to give 8-8 (317 mg, 19.0%) and 8-7 (250 mg,15.0%) as white solid. ¹H NMR (8-8): (400 MHz, CDCl₃) δ 5.30 (s, 1H),2.42 (d, J=12.4 Hz, 1H), 2.01-1.99 (m, 3H), 1.89-1.65 (m, 4H), 1.59-1.58(m, 1H), 1.51-1.26 (m, 9H), 1.20-1.05 (m, 12H), 1.04-0.99 (m, 4H),0.94-0.88 (m, 10H), 0.68 (s, 3H). ¹H NMR (8-7): (400 MHz, CDCl₃) δ 5.30(d, J=3.6 Hz, 1H), 2.42 (d, J=12.4 Hz, 1H), 2.00-1.97 (m, 3H), 1.89-1.68(m, 4H), 1.58-1.25 (m, 10H), 1.19-1.08 (m, 10H), 1.03-0.98 (m, 4H),0.95-0.88 (m, 10H), 0.68 (s, 3H).

Preparation of 8-6.

A mixture of 8-8 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAc(30 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50° C. Thereaction mixture was filtered through a celite pad. The pad was washedwith EtOAc (50 mL). The filtrate was concentrated in vacuum and theresidue was purified by silica gel column eluted with PE/EtOAc=20/1 togive 8-6 (85.9 mg, 42.8%) as a white solid and 8-6A (17.6 mg, 8.8%) as awhite solid. ¹H NMR (8-6) (400 MHz, CDCl₃), δ (ppm) 1.97-1.94 (d, 1H,J=12.8 Hz), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 3H), 1.54-1.45 (m, 3H),1.36-1.19 (m, 13H), 1.16-0.96 (m, 12H), 0.92-0.87 (m, 10H), 0.80 (s,3H), 0.68-0.65 (m, 4H). ¹H NMR (8-6A) (400 MHz, CDCl₃), δ (ppm)1.98-1.95 (d, 1H, J=10.8 Hz), 1.88-1.79 (m, 3H), 1.71-1.59 (m, 3H),1.53-1.48 (m, 2H), 1.42-1.31 (m, 6H), 1.27-0.96 (m, 20H), 0.92-0.87 (m,12H), 0.80 (s, 3H), 0.64 (s, 3H).

Preparation of 8-5

A mixture of 8-7 (150 mg, 0.348 mmol, 1.0 eq) and Pd/C (75 mg, cat.) inEtOAc (20 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The reaction mixture was filtered through a celite pad. The pad waswashed with EtOAc (50 mL). The filtrate was concentrated in vacuum andthe residue was purified by silica gel column eluted with PE/EtOAc=20/1to give 8-5 (89.0 mg, 44.3%) as a white solid and 8-5A (4.6 mg, 2.3%) asa white solid. ¹H NMR (8-5) (400 MHz, CDCl₃), δ (ppm) 1.97-1.94 (d, 1H,J=12.8 Hz), 1.88-1.79 (m, 1H), 1.71-1.61 (m, 3H), 1.54-1.45 (m, 3H),1.36-1.19 (m, 13H), 1.16-0.96 (m, 12H), 0.92-0.87 (m, 10H), 0.80 (s,3H), 0.68-0.65 (m, 4H). ¹H NMR (8-5A) (400 MHz, CDCl₃), δ (ppm)1.98-1.95 (d, 1H, J=10.8 Hz), 1.91-1.79 (m, 3H), 1.72-1.64 (m, 2H),1.54-1.50 (m, 1H), 1.46-1.00 (m, 28H), 0.96-0.87 (m, 12H), 0.64 (s, 3H).

Example 9

Preparation of 9-2.

To a solution of compound 9-1 (100 mg, 0.25 mmol) in THF (2 mL) wasadded dropwise a solution of CyclopropylmagnesiumBromide (2.5 mL, 2.5mmol, 1 M in THF) at room temperature during a period of 10 min undernitrogen. Then the reaction mixture was stirred at room temperature for12 h. TLC showed that the starting material was consumed completely. Themixture was poured into aqueous saturated NH₄Cl solution (20 mL) andextracted with EtOAc (50 mL×2). The combined organic phases were driedover Na₂SO₄, and the solvent was evaporated to afford crude product. Thecrude product purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=10:1) to give the product 9-2 (33 mg, 30%)as white powder. ¹H NMR: (400 MHz, CDCl3) δ: 5.31 (d, J=5.2 Hz, 1H),2.42 (d, J=12.8 Hz, 1H), 2.08-1.93 (m, 3H), 1.90-1.65 (m, 3H), 1.62-1.27(m, 13H), 1.22-1.08 (m, 11H), 1.01 (s, 3H), 1.00-0.85 (m, 6H), 0.68 (s,3H), 0.40-0.25 (m, 4H).

Preparation of 9-3 and 9-4

Compound 9-2 (200 mg, 0.46 mmol) was separated by SFC to get 9-3 (90 mg)and 9-4 (100 mg) as white solid, (total yield: 95%). ¹H NMR: (9-3) (400MHz, CDCl₃) δ 5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.02-1.99 (m, 3H),1.95-1.60 (m, 3H), 1.50-1.25 (m, 9H), 1.20-1.05 (m, 11H), 1.02-0.93 (m,11H), 0.68 (s, 3H), 0.35-0.28 (m, 4H). ¹H NMR: (9-4) (400 MHz, CDCl₃) δ5.31-5.30 (m, 1H), 2.44-2.41 (m, 1H), 2.02-1.95 (m, 3H), 1.93-1.60 (m,3H), 1.50-1.25 (m, 10H), 1.20-1.05 (m, 11H), 1.02-0.93 (m, 11H), 0.68(s, 3H), 0.36-0.24 (m, 4H)

Preparation of 9-7

To a solution of compound 9-3 (100 mg, 0.23 mmol) in EtOAc (8 mL) wasadded Pd/C (10%, 200 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. Then the mixture was stirredunder H₂ (50 psi) at 50 OC for 24 hours. The suspension was filteredthrough a pad of celite and the pad was washed with EtOAc (30 mL×2). Thecombined filtrates were concentrated to dryness to give the crudeproduct, which was purified by column chromatography on silica gel(petroleum ether:ethyl acetate=20:1) to afford 9-7 (27.8 mg, 27.8%) aswhite solid. ¹H NMR: (9-7) (400 MHz, CDCl₃) δ 1.97-1.94 (m, 1H),1.90-1.80 (m, 1H), 1.64-1.57 (m, 3H), 1.54-1.30 (m, 7H), 1.28-0.85 (m,25H), 0.80 (s, 3H), 0.65-0.60 (m, 4H), 0.36-0.33 (m, 4H). ¹H NMR: (9-7A)(400 MHz, CDCl₃) δ 1.95-1.83 (m, 4H), 1.70-1.57 (m, 1H), 1.45-1.11 (m,22H), 1.05-0.85 (m, 17H), 0.65 (s, 3H), 0.36-0.34 (m, 4H)

Preparation of 9-8

To a solution of compound 9-4 (100 mg, 0.23 mmol) in EtOAc (8 mL) wasadded Pd/C (10%, 200 mg) under N₂. The suspension was degassed undervacuum and purged with H₂ several times. Then the mixture was stirredunder H₂ (50 psi) at 50° C. for 24 hours. The suspension was filteredthrough a pad of celite and the pad was washed with EtOAc (30 mL×2). Thecombined filtrates were concentrated to dryness to give the crudeproduct, which was purified by HPLC to afford 9-8 (18.3 mg, 18%) aswhite solid. ¹H NMR: (9-8) (400 MHz, CDCl₃) δ 1.97-1.94 (m, 1H),1.90-1.80 (m, 1H), 1.60-1.57 (m, 3H), 1.54-1.20 (m, 16H), 1.19-0.82 (m,16H), 0.80 (s, 3H), 0.65-0.60 (m, 4H), 0.36-0.28 (m, 4H)

Example 10

Preparation of 10-2.

To a solution of compound 10-1 (100 mg, 0.25 mmol) in toluene (8 mL) wasadded dropwise a solution of ethynylmagnesium bromide (4 mL, 2.0 mmol,0.5 M in THF) at room temperature during a period of 10 min undernitrogen. Then the reaction mixture was stirred at 50° C. over night.TLC showed that the starting material was consumed completely. Themixture was poured into aqueous saturated NH₄Cl solution (10 mL) andextracted with EtOAc (25 mL×2). The combined organic phases were driedover Na₂SO₄, and the solvent was evaporated to afford crude product. Thecrude product purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=10:1) to give the product 10-2 (80 mg,74.98%) as white powder. ¹H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz,1H), 2.43-2.40 (m, 2H), 2.06-1.81 (m, 5H), 1.80-1.67 (m, 3H), 1.67-1.59(m, 2H), 1.49 (s, 3H), 1.48-1.42 (m, 2H), 1.40-1.24 (m, 4H), 1.20-1.13(m, 2H), 1.10 (s, 3H), 0.96-0.92 (m, 3H), 0.69 (s, 3H).

Preparation of 10-3 and 10-4.

Compound 10-2 (350 mg, 0.849 mmol) was split by SFC to get 10-3 (82 mg)and 10-4 (94 mg) as white powder (total yield: 50%). ¹H NMR (^(a)10-3)(400 MHz, CDCl₃), δ 5.29 (d, J=5.2 Hz, 1H), 2.43-2.40 (m, 2H), 2.05-0.95(m, 38H), 0.68 (s, 3H). ¹H NMR (10-4) (400 MHz, CDCl₃), δ5.29 (d, J=5.2Hz, 1H), 2.43-2.40 (m, 2H), 2.05-0.95 (m, 38H), 0.68 (s, 3H).

Preparation of 10-5.

To a solution of compound 10-1 (3.0 g, 7.76 mmol) in a mixture solventof EtOAc (20 mL) and EtOH (10 mL) was added Pd/C (33%, 1.0 g) under N₂.The suspension was degassed under vacuum and purged with H₂ severaltimes. Then the mixture was stirred under H₂ (50 psi) at 50° C. for 6days. The suspension was filtered through a pad of celite and the padwas washed with EtOAc (100 mL×3). The combined filtrates wereconcentrated to dryness to give the crude product, which was purified bycolumn chromatography on silica gel (petroleum ether:ethyl acetate=20:1)to afford 10-5 (1.7 g, 56%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ2.48-2.44 (m, 1H), 2.43-2.40 (m, 1H), 2.13 (s, 3H), 1.95-1.25 (m, 20H),1.23 (s, 3H), 1.22-1.00 (m, 8H), 0.90-0.88 (d, J=6.4 Hz, 3H), 0.80 (s,3H), 0.63-0.60 (m, 4H)

Preparation of 10-6.

To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 mL) was addedethynylmagnesium bromide (28.2 mL, 14.1 mmol) dropwise at 0° C. underN₂. Then the reaction mixture was stirred at room temperature for 12hours. TLC showed the starting material was consumed completely. Themixture was quenched by saturated aqueous NH₄Cl (80 mL) and extractedwith EtOAc. The organic phase was washed with brine, dried overanhydrous Na₂SO₄ then concentrated by vacuum. The residue was purifiedby column chromatography on silica gel (petroleum ether:ethylacetate=15:1) to afford 10-6 (380 mg, 64%) as a white solid. ¹H NMR:(400 MHz, CDCl₃) δ 2.42 (s, 1H), 1.97-1.48 (m, 14H), 1.47 (s, 3H),1.29-1.26 (m, 7H), 1.24 (s, 3H), 1.23-0.94 (m, 7H), 0.93-0.92 (d, J=6.4Hz, 3H), 0.80 (s, 3H), 0.65-0.62 (m, 4H)

Preparation of 10-6-BZ

To a solution of 10-6 (250 mg, 0.60 mmol) in pyridine (3 mL) was addedBzCl (168 mg, 1.2 mmol) dropwise at room temperature. Then the reactionmixture was stirred at 45° C. for 12 hours. TLC showed the startingmaterial was consumed completely. The mixture was quenched by saturatedaqueous water and extracted with EtOAc. The combined organic phase waswashed with 1 M HCl (20 mL) and brine, dried over anhydrous Na₂SO₄ thenconcentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=80:1) to10-6-Bz (200 mg, 64%) as a white solid.

Preparation of 10-8-Bz and 10-9-Bz

Compound 10-6-Bz (200 mg, 0.39 mmol) was split by SFC to afford 10-8-Bz(80 mg, 40%) and 10-9-Bz (70 mg, 35%) as white solid. ¹H NMR: (10-8-Bz)(400 MHz, CDCl₃) δ 7.99-7.98 (d, J=7.6 Hz, 2H), 7.51-7.49 (d, J=7.2 Hz,1H), 7.42-7.38 (t, J=7.2 Hz, 2H), 2.42 (s, 1H), 2.05-1.68 (m, 8H), 1.65(s, 3H), 1.60-1.49 (m, 7H), 1.48 (s, 3H), 1.45-1.11 (m, 16H), 0.94-0.92(d, J=6.4 Hz, 3H), 0.87 (s, 3H), 0.66-0.62 (m, 4H). ¹H NMR: (10-9-Bz)(400 MHz, CDCl₃) δ 7.99-7.98 (d, J=7.6 Hz, 2H), 7.51-7.49 (d, J=7.2 Hz,1H), 7.42-7.38 (t, J=7.6 Hz, 2H), 2.43 (s, 1H), 2.05-1.67 (m, 8H), 1.65(s, 3H), 1.60-1.48 (m, 5H), 1.47 (s, 3H), 1.45-1.20 (m, 11H), 1.19-0.95(m, 9H), 0.94-0.92 (d, J=6.8 Hz), 0.87 (s, 3H), 0.66-0.62 (m, 4H)

Preparation of 10-8

To a solution of compound 10-8-Bz (80 mg, 0.15 mmol) in a mixturesolvent of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH(180 mg, 7.5 mmol) in H₂O (1.5 mL). The mixture was stirred at 40° C.for 3 days. TLC showed the starting material was consumed completely.The reaction mixture was treated with water and extracted with EtOAc.The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ then concentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=8:1) toafford 10-8 (57 mg, 92%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ2.42 (s, 1H), 1.93-1.49 (m, 11H), 1.48 (s, 3H), 1.35-1.20 (m, 16H),1.19-0.94 (m, 5H), 0.93-0.92 (d, J=6.4 Hz, 3H), 0.80 (s, 3H), 0.65-0.62(m, 4H)

Preparation of 10-9

To a solution of compound 10-9-Bz (70 mg, 0.14 mmol) in a mixturesolvent of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH(168 mg, 7.0 mmol) in H₂O (1.5 mL). The mixture was stirred at 40° C.for 3 days. TLC showed the starting material was consumed completely.The reaction mixture was treated with water and extracted with EtOAc.The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ then concentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=8:1) toafford 10-9 (53 mg, 91%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ2.42 (s, 1H), 1.93-1.49 (m, 11H), 1.48 (s, 3H), 1.29-0.94 (m, 21H),0.93-0.92 (d, J=6.4 Hz, 3H), 0.80 (s, 3H), 0.65-0.62 (m, 4H)

Preparation of 10-7

To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 mL) was addedvinylmagnesium bromide (9.87 mL, 9.87 mmol) dropwise at 0° C. under N₂.Then the reaction mixture was stirred at room temperature for 12 hours.TLC showed the starting material was consumed completely. The mixturewas quenched by saturated aqueous NH₄Cl (30 mL) and extracted withEtOAc. The organic phase was washed with brine, dried over anhydrousNa₂SO₄ then concentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=15:1) toafford 10-7 (300 mg, 51%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ5.93-5.86 (m, 1H), 5.20-5.16 (d, J=17.6 Hz, 1H), 5.05-5.02 (d, J=10.8Hz, 1H), 1.96-193 (m, 1H), 1.60-1.57 (m, 4H), 1.51-1.20 (m, 20H),1.19-1.00 (m, 8H), 0.91-0.89 (d, J=6 Hz, 3H), 0.80 (s, 3H), 0.64-0.60(m, 4H)

Preparation of 10-7-Bz.

To a solution of 10-7 (220 mg, 0.53 mmol) in pyridine (3 mL) was addedBzCl (150 mg, 1.06 mmol) dropwise at room temperature. Then the reactionmixture was stirred at 40° C. for 12 hours. TLC showed the startingmaterial was consumed completely. The mixture was quenched by saturatedaqueous water and extracted with EtOAc. The combined organic phase waswashed with 1 M HCl (30 mL) and brine, dried over anhydrous Na₂SO₄ thenconcentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=80:1) toafford 10-7-Bz (150 mg, 54%) as a white solid.

Preparation of 10-10-Bz and 10-11-Bz

Compound 10-7-Bz (190 mg, 0.37 mmol) was split by SFC to get 10-10-Bz(75 mg, 39%) and 10-11-Bz (70 mg, 37%) as white solid. ¹H NMR:(10-10-Bz) (400 MHz, CDCl₃) δ 7.99-7.97 (d, J=7.2 Hz. 1H), 7.51-7.49 (d,J=7.6 Hz, 1H), 7.42-7.38 (t, J=8.0 Hz, 2H), 5.93-5.86 (dd, J₁=11.2 Hz,J₂=17.2, 1H), 5.21-5.16 (d, J=17.6 Hz, 1H), 5.05-5.02 (d, J=10.4 Hz,1H), 2.05-1.75 (m, 8H), 1.65-1.27 (m, 19H), 1.26 (s, 3H), 1.25-0.93 (m,10H), 0.91-0.90 (d, 6.0 Hz, 3H), 0.86 (s, 3H), 0.70-0.64 (m, 4H) ¹H NMR:(10-11-Bz) (400 MHz, CDCl₃) δ 7.99-7.97 (d, J=7.2 Hz, 1H), 7.51-7.49 (d,J=7.6 Hz, 1H), 7.42-7.38 (t, J=8.0 Hz, 2H), 5.93-5.86 (dd, J₁=10.8 Hz,J₂=17.6, 1H), 5.20-5.16 (d, J=17.2 Hz, 1H), 5.05-5.02 (d, J=10.4 Hz,1H), 2.05-1.75 (m, 8H), 1.65-1.27 (m, 10H), 1.26 (s, 3H), 1.25-0.93 (m,10H), 0.91-0.90 (d, 6.4 Hz, 3H), 0.86 (s, 3H), 0.70-0.64 (m, 4H)

Preparation of 10-10.

To a solution of compound 10-10-Bz (75 mg, 0.14 mmol) in a mixturesolvent of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH(168 mg, 7.0 mmol) in H₂O (1.5 mL). The mixture was stirred at 40° C.for 3 days. TLC showed the starting material was consumed completely.The reaction mixture was treated with water and extracted with EtOAc.The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ then concentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=8:1) toafford 10-10 (55 mg, 94%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ1.96-1.92 (m, 1H), 1.90-1.70 (m, 2H), 1.69-1.57 (m, 5H), 1.55-1.20 (m,18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H)

Preparation of 10-11-Bz.

To a solution of compound 10-11-Bz (70 mg, 0.13 mmol) in a mixturesolvent of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH(168 mg, 7.0 mmol) in H₂O (1.5 mL). The mixture was stirred at 40° C.for 3 days. TLC showed the starting material was consumed completely.The reaction mixture was treated with water and extracted with EtOAc.The combined organic phase was washed with brine, dried over anhydrousNa₂SO₄ then concentrated by vacuum. The residue was purified by columnchromatography on silica gel (petroleum ether:ethyl acetate=8:1) toafford 10-11 (49 mg, 91%) as a white solid. ¹H NMR: (400 MHz, CDCl₃) δ1.96-1.92 (m, 1H), 1.90-1.70 (m, 2H), 1.69-1.57 (m, 5H), 1.55-1.20 (m,18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H)

Preparation of 10-22 and 10-23.

To a solution of 10-14 (550 mg, 1.27 mmol) in THF (10 mL) was added NaH(254 mg, 6.36 mmol) at 0° C., and stirred at the same temperature for 30minutes. Then CH₃I (127 mg, 0.770 mmol) was added dropwise to themixture. The reaction was monitored by TLC. After 1 h, 127 mg of CH₃Iwas added in two portions. After stirring at room temperature for 1.5 h,the reaction mixture was quenched with aqueous NH₄Cl (20 mL), extractedwith EtOAc (20 mL×3), dried over Na₂SO₄ and concentrated to give crudeproduct. The crude product was purified by column chromatography onsilica gel (petroleum ether/ethyl acetate=15/1) to give 10-14 as a whitepowder. The diastereomeric pairs (340 mg) were separated by prep-SFC togive 10-22 (130 mg, 22.9%) as a white power and 10-23 (135 mg, 23.8%) asa white power. ¹H NMR (10-22): (400 MHz, CDCl₃) δ 5.30 (s, 1H),3.65-3.53 (m, 2H), 3.35 (s, 3H), 3.04 (br, 1H), 2.44-2.40 (d, 1H, J=13.6Hz), 2.02-1.95 (m, 3H), 1.86-1.64 (m, 5H), 1.62-1.58 (m, 1H), 1.52-1.23(m, 9H), 1.17-1.05 (m, 11H), 1.04-0.98 (m, 4H), 0.95-0.93 (d, 4H, J=6.8Hz), 0.68 (s, 3H). ¹H NMR (10-23): (400 MHz, CDCl3) 65.30 (s, 1H), 3.61(t, 2H, J=6.0 Hz), 3.35 (s, 3H), 3.04 (br, 1H), 2.44-2.40 (d, 1H, J=12.8Hz), 2.02-1.95 (m, 3H), 1.86-1.64 (m, 5H), 1.57-1.25 (m, 12H), 1.16-0.93(m, 17H), 0.68 (s, 3H).

Preparation of 10-17.

A mixture of 10-22 (100 mg, 0.224 mmol) and Pd/C (50 mg, cat.) in EtOAc(10 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50° C. Thereaction mixture was filtered through a celite pad. The pad was washedwith EtOAc (40 mL). The filtrate was concentrated in vacuum and theresidue was purified by silica gel column eluted with PE/EtOAc=15/1 togive 10-17 (68.4 mg, 68.1%) as a white solid. 1H NMR (10-17) (400 MHz,CDCl₃), δ 3.62-3.58 (m, 2H), 3.35 (s, 3H), 3.07 (br, 1H), 1.97-1.93 (d,1H, j=12.8 Hz), 1.83-1.74 (m, 2H), 1.69-1.55 (m, 5H), 1.50-1.43 (m, 3H),1.37-1.23 (m, 12H), 1.16-0.97 (m, 10H), 0.93-0.91 (d, 1H, J=6.0 Hz),0.80 (s, 3H), 0.68-0.64 (m, 3H).

Preparation of 10-19.

A mixture of 10-23 (100 mg, 0.224 mmol) and Pd/C (50 mg, cat.) in EtOAc(10 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50° C. Thereaction mixture was filtered through a celite pad. The pad was washedwith EtOAc (40 mL). The filtrate was concentrated in vacuum and theresidue was purified by silica gel column eluted with PE/EtOAc=15/1 togive 10-19 (68.6 mg, 68.3%) as a white solid. ¹H NMR (10-19) (400 MHz,CDCl₃), δ 3.60 (t, 2H, J=6.0 Hz), 3.35 (s, 3H), 3.07 (br, 1H), 1.97-1.94(d, 1H, J=12.8 Hz), 1.81-1.57 (m, 6H), 1.54-1.43 (m, 4H), 1.36-1.22 (m,12H), 1.16-0.97 (m, 10H), 0.92-0.91 (d, 1H, J=6.0 Hz), 0.80 (s, 3H),0.68-0.61 (m, 3H).

Preparation of 10-7.

To a solution of 10-6 (60 mg, 0.14 mmol) in EtOAc (2 mL) was addelindlar cat (24 mg). Then the mixture was stirred under hydrogen (1 atm)at room temperature for 1.5 hours. The mixture was filtered through apad of celite and the filtrate was evaporated under reduced pressure.The residue was purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=10:1) to afford the pure product 10-7 (26mg, 43.0%) as white powder. ¹H NMR: (400 MHz, CDCl3) δ 5.93-5.85 (m,1H), 5.20-5.16 (d, J=17.2 Hz, 1H), 5.05-5.02 (d, J=10.8 Hz, 1H),1.96-1.93 (m, 1H), 1.79-1.67 (m, 1H), 1.66-1.57 (m, 4H), 1.55-1.36 (m,11H), 1.35-1.27 (m, 9H), 1.26-0.97 (m, 8H), 0.96-0.89 (m, 3H), 0.81 (s,3H), 0.68-0.62 (m, 4H).

Preparation of Compound 10-12.

To a solution of 10-1 (50 mg, 0.13 mmol) in THF (2 mL), vinyl magnesiumbromide solution (1 mmol, 1 M in THF, 1 mL) was added drop-wise at −50°C. The reaction mixture was warmed to room temperature and stirred atroom temperature for 16 hours. TLC (petroleum ether:ethyl acetate=3:1)showed the reaction was finished, the reaction mixture was quenched withaq. saturated NH₄Cl solution (10 mL) and then extracted with EtOAc (10mL×3). The combined organic layer was washed with brine (10 mL×2), driedover anhydrous Na₂SO₄ and concentrated in vacuum. The residue waspurified by column chromatography on silica gel (eluent: petroleumether:ethyl acetate=15/1) to afford 10-12 (27 mg, 54%) as white powder.¹H NMR: (400 MHz, CDCl3) δ 5.94-5.86 (m, 1H), 5.30 (d, J=5.2 Hz, 1H),5.19 (d, J=17.2 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 2.42 (d, J=12.8 Hz,1H), 2.01-1.95 (m, 3H), 1.80-1.61 (m, 4H), 1.56-1.37 (m, 10H), 1.27 (s,3H), 1.18-1.13 (m, 3H), 1.11 (s, 3H), 1.10-1.04 (m, 3H), 1.01 (s, 3H),1.00-0.95 (m, 2H), 0.92 (d, —=6.4 Hz, 3H), 0.67 (s, 3H).

Preparation of 10-12A and 10-12B.

Compound 10-12 (350 mg, 0.84 mmol) was split by SFC to give 10-12A (160mg) and 10-12B (110 mg) as a white solid (total yield: 77%). ¹H NMR(10-12-A): (400 MHz, CDCl₃) δ 5.94-5.86 (m, 1H), 5.30 (d, J=5.2 Hz, 1H),5.19 (d, J=17.2 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 2.50-2.40 (m, 1H),2.05-0.85 (m, 36H), 0.67 (s, 3H). ¹H NMR (10-12-B): (400 MHz, CDCl₃) δ5.94-5.86 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 5.19 (d, J=17.2 Hz, 1H), 5.04(d, J=10.4 Hz, 1H), 2.50-2.40 (m, 1H), 2.05-0.85 (m, 36H), 0.67 (s, 3H).

Preparation of Compound 10-13.

To a solution of 10-12 (500 mg, 1.21 mmol) in THF (5 mL) was added 9-BBN(24.2 mL, 12.1 mmol) gradually at 0° C. under N₂ protection. The mixturewas stirred at 60° C. for 16 hours. Then the reaction mixture was cooledto 0° C., and 10% aqueous NaOH (10 mL), 30% H₂O₂ (5 mL) was added. Theresulting mixture was stirred at 0° C. for 2 hours. The reaction mixturewas quenched with aqueous Na₂S₂O₃ (10 mL), extracted with EtOAc (10mL×3), dried over Na₂SO₄ and concentrated to give crude product. Thecrude product was purified by pre-HPLC to give 10-13 (100 mg, 19.2%) aswhite solid. ¹H NMR: (300 MHz, CD₃OD) δ 5.32 (d, J=5.2 Hz, 1H), 3.70 (d,J=6.4 Hz, 2H), 2.51-2.35 (m, 1H), 2.14-1.84 (m, 4H), 1.82-1.26 (m, 16H),1.24-1.10 (m, 7H), 1.08-1.00 (m, 7H), 1.00-0.93 (m, 4H), 0.73 (s, 3H).

Preparation of Compound 10-14.

To a solution of 10-13 (50 mg, 0.11 mmol) in THF (5 mL) was added NaH(13.2 mg, 0.55 mmol) at 0° C., and stirred at the same temperature for30 minutes. Then CH₃I (78 mg, 0.55 mmol) was added drop-wise to themixture. The mixture was stirred at room temperature for 1 hour. Thereaction mixture was quenched with aqueous NH₄Cl (10 mL), extracted withEtOAc (10 mL×3), dried over Na₂SO₄ and concentrated to give crudeproduct. The crude product was purified by column chromatography onsilica gel (petroleum ether:ethyl acetate=5:1) to give 10-14 (13 mg,25.2%) as white powder. ¹H NMR: (300 MHz, CDCl₃) δ 5.23 (d, J=5.2 Hz,1H), 3.54 (d, J=6.4 Hz, 2H), 3.29 (s, 3H), 2.38-2.34 (m, 1H), 1.95-1.88(m, 3H), 1.74-1.58 (m, 5H), 1.52-1.19 (m, 14H), 1.10 (s, 3H), 1.09-1.05(m, 1H), 1.04 (s, 3H), 1.02-0.94 (m, 2H), 0.91 (s, 3H), 0.87 (d, J=6.4Hz, 3H), 0.61 (s, 3H).

Preparation of 10-20 and 10-21.

The crude product 10-13 was washed with EtOAc (30 mL) to give thediastereomeric pair (900 mg, 53.9%) as a white solid. The mixture (400mg) was separated by SFC to give 10-20 (30 mg, 4.0%) as a white solidand 10-21 (68 mg, 9.2%) as a white solid. ¹H NMR (10-20): (400 MHz,Methanol-d4) δ 5.28 (s, 1H), 3.69 (t, 2H, J=7.2 Hz), 2.42-2.39 (d, 1H,J=11.6 Hz), 2.04-1.90 (m, 5H), 1.78-1.28 (m, 17H), 1.17-1.02 (m, 12H),0.95-0.93 (d, 4H, J=6.8 Hz), 0.71 (s, 3H). ¹H NMR (10-21): (400 MHz,Methanol-d4) δ 5.28 (s, 1H), 3.68 (t, 2H, =7.2 Hz), 2.42-2.39 (d, 1H,f=11.6 Hz), 2.04-1.90 (m, 5H), 1.78-1.28 (m, 16H), 1.18-0.98 (m, 13H),0.95-0.93 (d, 4H, J=7.0 Hz), 0.71 (s, 3H).

Preparation of 10-16.

A mixture of 10-20 (20 mg, 0.046 mmol) and Pd/C (20 mg, cat.) in EtOAc(5 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50° C. Thereaction mixture was filtered through a celite pad. The pad was washedwith EtOAc (50 mL). The filtrate was concentrated in vacuum and theresidue was purified by silica gel column eluted with PE/EtOAc=5/1 togive 10-16 (7.6 mg, 39.3%) as a white solid. ¹H NMR (10-16) (400 MHz,Methanol-d4), δ 3.70 (t, 2H, J=7.2 Hz), 2.01-1.98 (d, 1H, J=12.4 Hz),1.93-1.82 (m, 1H), 1.72-1.57 (m, 5H), 1.53-1.39 (m, 5H), 1.35-0.99 (m,22H), 0.96-0.94 (d, 4H, J=6.4 Hz), 0.84 (s, 3H), 0.70-0.66 (m, 4H).

Preparation of 10-18.

A mixture of 10-21 (40 mg, 0.092 mmol, 1.0 eq) and Pd/C (20 mg, cat.) inEtOAc (5 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The reaction mixture was filtered through a celite pad. The pad waswashed with EtOAc (50 mL).

The filtrate was concentrated in vacuum and the residue was purified bysilica gel column eluted with PE/EtOAc=5/1 to give 10-18 (12.9 mg,32.1%) as a white solid. ¹H NMR (10-18) (400 MHz, Methanol-d4), δ 3.68(t, 2H, J=7.2 Hz), 1.99-1.96 (d, 1H, 1=12.4 Hz), 1.92-1.82 (m, 1H),1.68-1.58 (m, 5H), 1.52-1.41 (m, 5H), 1.37-0.97 (m, 22H), 0.94-0.92 (d,4H, J=6.4 Hz), 0.82 (s, 3H), 0.67-0.65 (m, 4H).

Example 11

Preparation of Compound 11-2.

To a solution of crude compound 11-1 (30 g, 77 mmol) in dichloromethane(200 mL) was added imidazole (10.4 g, 154 mmol) andtert-butylchlorodimethylsilane (13.8 g, 92 mmol). The mixture was thenstirred at 15° C. for 16 h. The mixture was washed with water, driedover anhydrous Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography on silica gel (petroleum ether:ethyl acetate=150:1to 80:1) to give crude product of 11-2 (38 g, 98%) as white solid.

Preparation of Compound 11-3.

To a solution of diisopropylamine (34.3 g, 340 mmol) in THF (1 L) wasadded butyl lithium (136 mL, 340 mmol, 2.5 M in hexane) under nitrogenatmosphere at −78° C. The mixture was then stirred at −78° C. for 10minutes and then 25° C. for 10 minutes and at last −78° C. for 10minutes. A solution of crude compound 11-2 (34 g, 68 mmol) in THF (100mL) was then added and stirred for 1 h at −78° C. To the mixture wasthen added triethyl phosphite (22.6 g, 136 mmol), the mixture was thenstirred under oxygen atmosphere for 3 h at −78° C. and then 16 h at 25°C. To the mixture was then added ammonium chloride (aq.). The organiclayer was separated, purified by column chromatography on silica gel(petroleum ether:ethyl acetate=10:1 to 3:1) to give crude product of11-3 (10 g, 28%) as yellow solid.

Preparation of Compound 11-4.

To a solution of crude 11-3 (10 g, 19 mmol) in dichloromethane (100 mL)was added Dess-Martin reagent (16 g, 38 mmol) at 0° C. under nitrogenatmosphere. The mixture was then stirred at 30° C. for 3 h. To themixture was then added a mixed solution of sodium bicarbonate and sodiumthiosulfate in water. The organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, concentrated under vacuum togive crude compound 11-4 as (5.9 g, 59%) white solid.

Preparation of Compound 11-5.

To a solution of crude 11-4 (5.9 g, 11 mmol) in THF (60 mL) was addedhydrogen chloride (aq., 6 mL, 6 mmol, 1M). The mixture was stirred at15° C. for 16 h. To the mixture was then added sodium bicarbonate (aq.).The organic layer was separated, dried over anhydrous sodium sulfate,concentrated under vacuum to give crude 11-5 (3.2 g, yield: 70%) aswhite solid.

Preparation of Compound 11-6.

To a solution of crude 11-5 (3.2 g, 7.9 mmol) in pyridine (50 mL),acetyl chloride (1.5 g, 19 mmol) was added dropwise at 0° C. asmonitored by TLC until the reaction was completed. To the mixture wasthen added water, concentrated under vacuum. To the residue was addedwater, extracted with dichloromethane. The organic layer was dried overanhydrous sodium sulfate, purified by column chromatography on silicagel (eluent: petroleum ether:ethyl acetate=100:1) to give crude 11-6(2.8 g, 79%) as white solid.

Preparation of Compound 11-7.

To a solution of crude 11-6 (2.8 g, 6.3 mmol) in dichloromethane (10 mL)was added diethylaminosulfur trifluoride (8 g, 50 mmol) at 0° C.dropwise. The mixture was then stirred for 16 h at 30° C. The mixturewas then added to sodium bicarbonate (aq.). The organic layer wasseparated, dried over anhydrous sodium sulfate, purified by columnchromatography on silica gel (eluent: petroleum ether:ethylacetate=100:1 to 33:1) to give crude 11-7 (2 g, 68%) as white solid.

Preparation of Compound 11-8.

To a solution of crude 11-7 (2 g, 4.2 mmol) in THF (10 mL) wad added asolution of lithium hydroxide monohydrate (900 mg, 21 mmol) in water (10mL) and then was added methanol (5 mL). The mixture was then stirred at30° C. for 16 h. The mixture was then concentrated under vacuum. To theresidue was added water, filtered. The solid was washed with water,dried under vacuum to give 11-8 (1.5 g, 85%) as white solid. ¹H NMR:(400 MHz, methanol-d4) δ 5.34 (d, J=5.2 Hz, 1H), 3.45-3.35 (m, 1H),2.30-2.10 (m, 3H), 2.10-1.68 (m, 7H), 1.68-1.44 (m, 6H), 1.35-1.28 (m,2H), 1.28-1.12 (m, 3H), 1.12-0.98 (m, 8H), 0.74 (s, 3H).

Preparation of Compound 11-9.

To a solution of 11-8 (1 g, 2.4 mmol) in methanol (15 mL) was addedhydrogen chloride (5 mL, 4 M in methanol). The mixture was stirred at30° C. for 15 minutes. Sodium bicarbonate (aq.) was added till pH=7. Themixture was then concentrated under vacuum. To the residue was addedwater, extracted with ethyl acetate, The organic layer was separated,dried over anhydrous sodium sulfate, concentrated under vacuum, purifiedby column chromatography on silica gel (eluent: petroleum ether:ethylacetate=10:1 to 5:1) to give 11-9 (970 mg, 93%) as white solid. ¹H NMR:(400 MHz, CDCl3) δ 5.34 (d, J=5.2 Hz, 1H), 3.87 (s, 3H), 3.60-3.48 (m,1H), 2.32-2.15 (m, 2H), 2.10-1.95 (m, 2H), 1.95-1.70 (m, 5H), 1.65-1.40(m, 8H), 1.30-0.90 (m, 13H), 0.70 (s, 3H).

Preparation of Compound 11-10.

To a solution of 11-9 (0.97 g, 2.3 mmol) in dichloromethane (50 mL) wasadded Dess-Martin reagent (2.3 g, 5.4 mmol) at 0° C. under nitrogenatmosphere. The mixture was then stirred at 30° C. for 3 h. To themixture was then added a mixed solution of sodium bicarbonate and sodiumthiosulfate in water. The organic layer was separated, washed withwater, dried over anhydrous sodium sulfate, concentrated under vacuum togive crude compound of 11-10 (1 g, 100%) as yellow oil.

Preparation of Compound 11-11 and 11-12.

To a solution of butylated hydroxytoluene (3.1 g, 14.2 mmol) in toluene(20 mL) was added Me₃Al (3.6 mL, 7.2 mmol, 2 M in toluene) at 15° C. Themixture was then stirred at 15° C. for 30 minutes. A solution of 11-11(0.9 g, 2.4 mmol) in toluene (5 mL) was added at −78° C. The mixture wasthen stirred at −78° C. for 1 h. methylmagnesium bromide (2.4 mL, 7.2mmol, 3M in ether) was then added at −78° C. The mixture was thenstirred at −78° C. for 1 hour. To the mixture was then added ammoniumchloride (aq.), filtered. The organic layer was separated and theaqueous phase was extracted with ethyl acetate. The combined organiclayer was dried over anhydrous sodium sulfate, concentrated undervacuum, purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=20:1 to 10:1) to give 240 mg of crude11-11 (yield: 28%) and 210 mg of crude 11-12 (yield: 25%). ¹H NMR (400MHz, CDCl3): δ 5.33-5.25 (m, 1H), 3.87 (s, 3H), 2.50-0.75 (m, 33H), 0.70(s, 3H). ¹H NMR: (400 MHz, CDCl3) δ 5.35-5.27 (m, 1H), 2.50-2.37 (m,1H), 2.32 (s, 3H), 2.20-0.75 (m, 32H), 0.70 (s, 3H).

Preparation of Compound 11-13.

To a solution of 11-12 (70 mg, 0.16 mmol) in ethanol (2 mL) was addedsodium borohydride (100 mg, 2.6 mmol) at 15° C. The mixture was stirredat 15° C. for 30 minutes. To the mixture was then added ammoniumchloride (aq.), concentrated under vacuum. To the residue was addedwater, extracted with ethyl acetate. The organic layer was separated,dried over anhydrous sodium sulfate, concentrated under vacuum, purifiedby column chromatography on silica gel (eluent: petroleum ether:ethylacetate=10:1 to 8:1) to give 11-13 (40 mg, 57%) as white solid. ¹H NMR:(400 MHz, methanol-d4) δ 5.35-5.28 (m, 1H), 3.88-3.68 (m, 1H), 2.49-2.37(m, 1H), 2.18-1.22 (m, 20H), 1.19 (d, J=6.0 Hz, 3H), 1.18-1.14 (m, 1H),1.11-1.08 (m, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 1.02-0.95 (m, 1H), 0.76(s, 3H).

Preparation of Compound 11-15 and 11-16. Diastereomeric mixture 11-13(30 mg, 0.071 mmol) was split by SFC to get 11-15 (12.2 mg) and 11-16(14.7 mg) as white powder (total yield: 90%). ¹H NMR (11-15): (400 MHz,MeOD) δ 5.32 (d, J=5.2 Hz, 1H), 3.85-3.72 (m, 1H), 2.50-2.40 (m, 1H),2.20-1.57 (m, I 1H), 1.52-0.85 (m, 23H), 0.78 (s, 3H). ¹H NMR (11-16):(400 MHz, MeOD) δ 5.32 (d, J=5.2 Hz, 1H), 3.85-3.72 (m, 1H), 2.50-2.40(m, 1H), 2.20-1.45 (m, 15H), 1.40-0.85 (m, 20H), 0.78 (s, 3H).

Preparation of Compound 11-19.

To a solution of 11-12 (70 mg, 0.16 mmol) in THF (2 mL) was addedmethylmagnesium bromide (1 mL, 3 mmol, 3M in ether) at −78° C. Themixture was stirred at 15° C. for 30 minutes. To the mixture was thenadded ammonium chloride (aq.), concentrated under vacuum. To the residuewas added water, extracted with ethyl acetate. The organic layer wasseparated, dried over anhydrous sodium sulfate, concentrated undervacuum, purified by column chromatography on silica gel (eluent:petroleum ether:ethyl acetate=10:1 to 8:1) to give 11-19 (39 mg, 55%) aswhite solid. ¹H NMR: (400 MHz, methanol-d4) δ 5.33-5.28 (m, 1H),2.48-2.38 (m, 1H), 2.12-1.70 (m, 17H), 1.23 (s, 6H), 1.20-1.12 (m, 3H),1.10 (d, J=6.4 Hz, 3H), 1.06 (s, 3H), 1.04 (s, 3H), 1.03-0.91 (m, 2H),0.76 (s, 3H).

Example 12 Preparation of Intermediate 0-9

Preparation of 0-2.

To a solution of compound 0-1 (100 g, 255 mmol, 1.0 eq) in dry MeOH (500mL) was added concentrated H₂SO₄ (14 mL). The mixture was heated toreflux overnight and then cooled to room temperature. The mixture wasquenched with aq. saturated NaHCO₃ solution (0.5 L) and then evaporatedto remove MeOH. The residue mixture was extracted with EtOAc (300 mL×3).The combined organic layers were washed with brine (200 mL), dried overNa₂SO₄ and evaporated to give the product (100 g crude, 96%) asoff-white powder. 1H NMR: (400 MHz, CDCl3) δ 4.09-4.02 (m, 1H), 3.66 (s,3H), 3.63-3.58 (m, 1H), 2.39-2.31 (m, 1H), 2.25-2.15 (m, 1H), 1.97-1.91(m, 1H), 1.91-1.55 (m, 10H), 1.52-1.02 (m, 14H), 0.95-0.88 (m, 6H), 0.62(s, 3H).

Preparation of 0-3.

To a solution of compound 0-2 (250 g, 615 mmol, 1.0 eq) in dry pyridine(0.8 L) was added a solution of TsCl (352 g, 1844 mmol, 3.0 eq) in drypyridine (200 mL). The mixture was stirred at room temperature for 18 h.Ice chips were added gradually to the mixture, and the precipitatedsolid was filtered, washed with aq. 10% HCl solution (400 mL×3) andwater (400 mL×2), and then evaporated to dryness to give crude product(500 g, crude) as a off-white powder, which was used to next stepdirectly

Preparation of 0-4.

A mixture of compound 0-3 (250 g crude), CH₃COOK (24 g, 245 mmol, 0.77eq), water (150 mL) and DMF (900 mL) was heated at reflux for 24 h. Thesolution was cooled to room temperature, with ice chips added gradually.The precipitated solid was filtered off and washed with water (100mL×2). The crude solid was purified on silica gel column (PE/EtOAc=8/1)to give compound 0-4 (40 g, yield 34.3% of two steps) as white solid. ¹HNMR (400 MHz, CDCl₃) δ 5.32-5.38 (m, 1H), 3.66 (s, 3H), 3.47-3.57 (m,1H), 2.16-2.41 (m, 4H), 1.93-2.04 (m, 2H), 1.74-1.92 (m, 4H), 1.30-1.59(m, 9H), 0.90-1.19 (m, 12H), 0.68 (s, 3H)

Preparation of 0-5.

To a solution of compound 0-4 (33 g, 85 mmol, 1.0 eq) in dry CH₂Cl₂ (700mL) was added Dess-Martin reagent (72 g, 170 mmol, 2.0 eq) in portionsat 0° C.

Then the reaction mixture was stirred at room temperature for 1 h. TLC(PE:EA=3:1) showed the starting material was consumed completely. Thereaction mixture were quenched with a saturated aqueous solution ofNaHCO₃/Na₂S₂O₃=1:3 (250 mL). The organic phase was washed with brine(200 mL×2) and dried over Na₂SO₄, and the solvent was evaporated toafford desired product (35 g, crude), which was used in the next stepwithout further purification.

Preparation of 0-6.

To a solution of MAD (0.42 mol, 3.0 eq) in toluene, freshly prepared byaddition of a solution of Me₃Al (210 mL, 0.42 mmol, 2 M in hexane) to astirred solution of 2,6-di-tert-butyl-4-methylphenol (185 g, 0.84 mol)in toluene (200 mL) followed by stirring for 1 h at room temperature,was added dropwise a solution of compound 0-5 (54 g, 0.14 mol, 1.0 eq)in toluene (200 mL) at −78° C. under nitrogen. Then the reaction mixturewas stirred for 30 min, a solution of MeMgBr (140 mL, 0.42 mol, 3.0 eq,3 M in ether) was added dropwise at −78° C. The reaction mixture waswarmed to −40° C. and stirred at this temperature for 3 h. TLC(PE:EA=3:1) showed that the starting material was consumed completely.The mixture was poured into aqueous saturated NH₄Cl solution (100 mL)and extracted with EtOAc (300 mL×2). The combined organic phases weredried over Na₂SO₄, and the solvent was evaporated to afford crudeproduct. The crude product was purified on silica gel chromatographyeluted with PE:EA=10:1 to give the pure target (30 g, 53%) as whitepowder. ¹H NMR: (400 MHz, CDCl3) δ 5.31-5.29 (m, 1H), 3.66 (s, 3H),2.39-2.33 (m, 2H), 2.24-2.22 (m, 1H), 1.99-1.95 (m, 3H), 1.85-1.68 (m,4H), 1.59-1.40 (m, 8H), 1.31-1.26 (m, 2H), 1.17-1.01 (m, 11H), 0.93-0.91(m, 4H), 0.67 (s, 3H).

Preparation of 0-7.

To a solution of compound 0-6 (30.0 g, 74.51 mmol) in THF/H₂O (800 mL,1/1) was added LiOH.H₂O (17.51 g, 417.28 mmol). The reaction was stirredat room temperature for 18 h. TLC (PE/EA=2/1) showed that compound 0-6was consumed completely. The mixture was concentrated in vacuum, dilutedwith water (2 L), and then acidified to pH=4 with 1 M aqueous HCl. Theprecipitate was collected by filtration and dried in vacuum to give theproduct compound 0-7 (33 g, crude) as off-white solid. ¹H NMR: (400 MHz,CDCl3) δ 5.31-5.30 (m, 1H), 2.44-2.36 (m, 2H), 2.29-2.24 (m, 1H),2.01-1.95 (m, 3H), 1.87-1.71 (m, 5H), 1.61-1.56 (m, 2H), 1.50-1.32 (m,8H), 1.17-1.09 (m, 7H), 1.01 (s, 3H), 0.95-0.93 (m, 4H), 0.68 (s, 3H).

Preparation of 0-8.

A mixture of compound 0-7 (32.0 g, 82.35 mmol),N,O-dimethylhydroxylamine (16.07 g, 164.70 mmol), HATU (37.57 g, 98.82mmol) and Et₃N (46.0 mL, 329.40 mmol) in 500 mL anhydrous CH₂Cl₂ wasstirred for 18 h at room temperature. TLC showed the reaction wascompleted. Then CH₂Cl₂ was added to the mixture and the resultingsolution was washed with water, 1 N HCl aqueous, saturated aqueousNaHCO₃ and brine, dried over anhydrous Na₂SO₄, filtered andconcentrated, purified by silica gel (PE:EtOAc=10:1 to 3:1) to affordthe target compound 0-8 (17.0 g, yield: 47.8%) as off-white solid. ¹HNMR: (400 MHz, CDCl3) δ 5.31-5.29 (m, 1H), 3.69 (s, 3H), 3.17 (s, 3H),3.03 (s, 2H), 2.47-2.29 (m, 3H), 2.04-1.68 (m, 7H), 1.60-1.43 (m, 7H),1.38-1.30 (m, 2H), 1.20-1.08 (m, 6H), 1.03-0.91 (m, 8H), 0.68 (s, 3H).

Preparation of Key Intermediate 0-9.

To a solution of compound 0-8 (17.0 g, 39.38 mmol) in 300 mL anhydrousTHF was added dropwise MeMgBr (65.6 mL, 196.92 mmol, 3 M in ether) underN₂ at 0° C. After the addition was completed, the reaction mixture wasstirred for 2 h at room temperature. TLC showed the reaction wascompleted. Then saturated aqueous NH₄Cl was slowly added to the mixtureat 0° C., then the mixture was poured to water, extracted with EtOAc(2*200 mL), the organic layers were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated, purified on silica gel(PE:EtOAc=20:1 to 6:1) to afford the target compound 0-9 (11.0 g, yield:72%) as white solid. ¹H NMR: (400 MHz, CDCl3) δ 5.31-5.30 (m, 1H),2.50-2.30 (m, 3H), 2.17 (s, 2H), 2.14 (s, 3H), 2.02-1.94 (m, 3H),1.88-1.67 (m, 4H), 1.61-1.58 (m, 1H), 1.56-1.49 (m, 5H), 1.47-1.41 (m,2H), 1.31-1.11 (m, 7H), 1.08-0.91 (m, 8H), 0.68 (s, 3H).

Assay Methods

Compounds of the present invention can be evaluated using various invitro and in vivo assays described in the literature; examples of whichare described below.

The following examples are offered to illustrate the biological activityof the compounds, pharmaceutical compositions, and methods providedherein and are not to be construed in any way as limiting the scopethereof.

NMDA Potentiation

NMDA potentiation was assessed using either whole cell patch clamp ofmammalian cells which expressed NMDA receptors, or using two-electrodevoltage clamp (TEVC) of Xenopus Laevis oocytes expressing NMDAreceptors.

Whole-Cell Patch Clamp of Mammalian Cells

The whole-cell patch-clamp technique was used to investigate the effectsof compounds (0.1 mM and 1.0 mM) on the NMDA receptor (GRIN1/GRIN2Asubunits) expressed in HEK cells. NMDA/Glycine peak and steady-statecurrents were recorded from stably transfected cells expressing the NMDAreceptor and the modulatory effects of the test items on these currentswere investigated. Results are shown on Table 1.

Cells were stably transfected with human GRIN1 (variant NR1-3). Thesecells were transiently transfected (Lipofectamine™) with GRIN2A cDNA andCD8 (pLeu) antigene cDNA. About 24-72 hours following transfection 1 μlDynabeads M-45 CD8 was added to identify successfully transfected cells(Jurman et al., Biotechniques (1994) 17:876-881). Cells were passaged toa confluence of 50-80%. Cells were seeded onto Poly-L-Lysine coatedcover slips covered with culture complete medium in a 35 mm culturedish. Confluent clusters of cells are electrically coupled (Pritchett etal., Science (1988), 242:1306-8). Because responses in distant cells arenot adequately voltage clamped and because of uncertainties about theextent of coupling (Verdoorn et al., Neuron (1990), 4:919-28), cellswere cultivated at a density that enables single cells (without visibleconnections to neighboring cells) to be measured. Cells were incubatedat 37° C. in a humidified atmosphere with 5% CO₂ (rel. humidity about95%). The cells were continuously maintained in and passaged in sterileculture flasks containing a 1:1 mixture of Dulbecco's modified eaglemedium and nutrient mixture F-12 (D-MEM/F-12 1×, liquid, withL-Glutamine) supplemented with 9% fetal bovine serum and 0.9%Penicillin/Streptomycin solution. The complete medium was supplementedwith 3.0 μg/ml Puromycin.

Whole cell currents were measured with HEKA EPC-10 amplifiers usingPatchMaster software. Cell culture dishes for recordings were placed onthe dish holder of the microscope and continuously perfused (1 ml/min)with “bath solution” (NaCl 137 mM, KCl 4 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM,HEPES 10 mM, D-Glucose 10 mM, pH (NaOH) 7.4). All solutions applied tocells including the pipette solution were maintained at room temperature(19° C.-30° C.). After formation of a Gigaohm seal between the patchelectrodes and transfected individual HEK 293 cells (pipette resistancerange: 2.5 MΩ-6.0 MΩ; seal resistance range:>1 GΩ) the cell membraneacross the pipette tip was ruptured to assure electrical access to thecell interior (whole-cell patch-configuration). At this point the bathsolution is switched to “NMDA bath solution” (NaCl 137 mM, KCl 4 mM,CaCl₂ 2.8 mM, HEPES 10 mM, D-Glucose 10 mM, Cremophore 0.02%, pH (NaOH)7.4). NMDA inward currents were measured upon application of 30 μM NMDA(and 5.0 M Glycine) to patch-clamped cells (2 applications) for 5 s. Thecells were voltage clamped at a holding potential of −80 mV. For theanalysis of test articles, NMDA receptors were stimulated by 30 μM NMDAand 5.0 μM Glycine after sequential pre-incubation of increasingconcentrations of the test article. Pre-incubation duration was 30 s.Stimulation duration was 5 s Test articles were dissolved in DMSO toform stock solutions of 0.1 mM and 1 mM. Test articles were diluted to0.1 μM and 1 μM in “NMDA bath solution”. Both concentrations of testarticles were tested on each cell. The same concentration was applied atleast three times or until the steady state current amplitude wasreached. Every day one cell was tested with 50 μM PREGS (positivecontrol) using the same application protocol to test whether cells weresuccessfully transfected with NMDA receptors.

TABLE 1 NMDA 1a2A NMDA 1a2A (%) Potentiation (%) Potentiation Structure0.1 uM 1 uM

A C

A B

B D

B C

A B

A A

C C

B C

B C

B C

A B

B C

B D

C C

A B

C C

A B

B C

C C For Table 1, “A” indicates 10-75% potentiation, “B” indicatespotentiation of >75% to 150%, and “C” indicates potentiation of >150 to250%; and “D indicates potentiation of >250%.

Oocytes

The Two Electrode Voltage Clamp (TEVC) technique was used to investigatethe effects of compounds (10 μM) on the NMDA receptor (GRIN1/GRIN2A)expressed in Xenopus oocytes. Glutamate/Glycine peak and steady-statecurrents were recorded from oocytes that expressed the NMDA receptor andthe modulatory effects of the test items on these currents wereinvestigated. Results are shown on Table 2.

Ovaries were harvested from Xenopus Laevis females that had been deeplyanesthetized by cooling at 4° C. and immersion in Tricainemethanesulfonate (MS-222 at a concentration of 150 mg/L) in sodiumbicarbonate (300 mg/L). Once anesthetized the animal was decapitated andpithed following the rules of animal rights from the Geneva canton. Asmall piece of ovary was isolated for immediate preparation while theremaining part was placed at 4° C. in a sterile Barth solutioncontaining in mM NaCl 88, KCl 1, NaHCO₃ 2.4, HEPES 10, MgSO₄.7H₂O 0.82,Ca(NO)₂.4H₂O 0.33, CaCl₂.6H₂O 0.41, at pH 7.4, and supplemented with 20μg/ml of kanamycin, 100 unit/ml penicillin and 100 g/ml streptomycin.All recordings were performed at 18° C. and cells were super-fused withmedium containing in mM: NaCl 82.5, KCl 2.5, HEPES 5, CaCl₂.2H₂O, 0.6H₂O1, pH 7.4.

Oocytes were injected with either cDNAs encoding for the human GRIN1 andGRIN2A subunits, using a proprietary automated injection device (Hogg etal., J. Neurosci. Methods, (2008) 169: 65-75) and receptor expressionwas assessed using electrophysiology at least two days later. The ratioof cDNA injection for GRIN I and GRIN2A was 1:1. Electrophysiologicalrecordings were made using an automated process equipped with standardTEVC and data were captured and analyzed using a proprietary dataacquisition and analysis software running under Matlab (Mathworks Inc.).The membrane potential of the oocytes was maintained at −80 mVthroughout the experiments. To explore the effects of proprietarycompounds, currents were evoked by applying 3 μM Glutamate and 10 μMGlycine for 10 s. Oocytes were then washed for 90 s before being exposedto the test article at a concentration of 10 μM for 120 s. Followingthis, 3 μM Glutamate and 10 μM Glycine were immediately reapplied for 10s. Potentiation of both the peak current and the steady state currentwas assessed. For statistical analysis values were computed either withExcel (Microsoft) or Matlab (Mathworks Inc.). To obtain meanmeasurements with standard deviations, all experiments were carried outusing at least three cells.

Glutamate was prepared as a concentrated stock solution (10⁻¹ M) inwater and then diluted in the recording medium to obtain the desiredtest concentration. Glycine was prepared as a stock solution at 1 M inwater. Compounds were prepared as stock solution (10⁻² M) in DMSO andthen diluted in the recording medium to obtain the desired testconcentration. Residual DMSO did not exceed the concentration of 1% aconcentration that has been shown to have no effects on Xenopus oocytesfunction.

TABLE 2 Structure % Potentiation at 10 μM

C

B

C

B

A

C

B

A

B

A

B

A

A

C

B

A

A

B

B

B

B

A

A

A

B

A

C

A

A

A

B

C

B

B

B

A

A

B

A

A

B

B

B

A

A

A

A

A

A

B

B

A

C

B

A

A

A

B

A

A

A

A

A For Table 2, “A” indicates 10-50% potentiation, “B” indicatespotentiation of >50% to 100%, and “C” indicates potentiation of >100%.

As shown in Table 1, compounds bearing a beta-hydrogen at C₅ aredisfavored compared to compounds bearing either alpha-hydrogen C₅ ordouble bond across C₅-C₆ due to loss of potentiation of the NMDAreceptor. This is illustrated by Comparison Compound 5 vs 4-6 and 4-7.The removal of the methyl at C₂₁ also results in significant loss ofNMDA potentiation, for example Comparison Compound 4 lost five foldpotentiation compared to Comparison Compound 3 when measured at 0.1 μMconcentration. Therefore the compounds in this selection bear both amethyl group in C₂₁ and either a double bond across C₅-C₆ or analpha-hydrogen in C₅. In addition, compounds in this selection showedimproved potency and limited maximum potentiation of the NMDA receptorwhen tested as high as 1 μM concentrations of compound (for exampleComparison Compound 2 vs 4-6 and 1-11). Such properties are expectedlimit the risk of inducing glutamate driven neurotoxicity relative tocompounds that achieve a greater maximum potentiation of the NMDAreceptor.

Other Embodiments

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: R¹ issubstituted or unsubstituted aliphatic; R² is hydrogen, halogen,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedcyclopropyl, or —OR^(A2), wherein R^(A2) is hydrogen or substituted orunsubstituted alkyl; R^(3a) is hydrogen or —OR^(A3), wherein R^(A3) ishydrogen or substituted or unsubstituted alkyl, and R^(3b) is hydrogen;or R^(3a) and R^(3b) are joined to form an oxo (═O) group; R⁴ ishydrogen, substituted or unsubstituted alkyl, or halogen; X is—C(R^(X))₂— or —O—, wherein R^(X) is hydrogen or fluorine, or one R^(X)group and R^(5b) are joined to form a double bond; each instance ofR^(5a) and R^(5b) is independently hydrogen or fluorine; R^(6a) is anon-hydrogen group selected from the group consisting of substituted andunsubstituted alkyl, substituted and unsubstituted alkenyl, substitutedand unsubstituted alkynyl, substituted and unsubstituted carbocyclyl,substituted and unsubstituted heterocyclyl, substituted andunsubstituted aryl, and substituted and unsubstituted heteroaryl group,wherein the non-hydrogen group is optionally substituted with fluorine;and R^(6b) is hydrogen or a substituted or unsubstituted alkyl groupoptionally substituted with fluorine;

represents a single or double bond, provided if a single bond ispresent, then the hydrogen at C5 is in the alpha configuration; andfurther provided that: (1) at least one of R^(X), R^(5a), and R^(5b) isfluorine; or (2) at least one of R^(6a) and R^(6b) is a non-hydrogengroup substituted with a fluorine; or (3) R^(6a) is a non-hydrogen groupcomprising between two and ten carbon atoms.
 2. The compound of claim 1,wherein R¹ is unsubstituted C₁₋₃ alkyl.
 3. The compound of claim 2,wherein R¹ is —CH₃, —CH₂CH₃, or —CH₂CH₂CH₃.
 4. The compound of claim 1,wherein R² is hydrogen.
 5. The compound of claim 1, wherein R^(3a) andR^(3b) are both hydrogen.
 6. The compound of claim 1, wherein R⁴ ishydrogen. 7-11. (canceled)
 12. The compound of claim 1, wherein R^(5a)and R^(5b) are both hydrogen.
 13. The compound of claim 1, wherein atleast one of R^(5a) and R^(5b) is fluorine.
 14. (canceled)
 15. Thecompound of claim 1, wherein R^(6a) is a non-hydrogen group substitutedwith fluorine.
 16. (canceled)
 17. The compound of claim 1, whereinR^(6a) is a non-hydrogen group substituted with one or more —OR^(A6)groups, wherein R^(A6) is hydrogen or substituted or unsubstitutedalkyl.
 18. (canceled)
 19. The compound of claim 1, wherein R^(6a) is asubstituted or unsubstituted C₂₋₄ alkyl, substituted or unsubstitutedC₂₋₃ alkenyl, substituted or unsubstituted C₂₋₃ alkynyl, or substitutedor unsubstituted C₃ carbocyclyl.
 20. The compound of claim 1 whereinR^(6b) is hydrogen.
 21. The compound of claim 1 wherein R^(6b) is —CH₃or —CF₃.
 22. The compound of claim 1, wherein R^(6a) is —CF₃ and R^(6b)is hydrogen or C₁₋₄ alkyl.
 23. The compound of claim 1, wherein R^(6a)is a non-hydrogen group substituted with fluorine, and R^(6b) is —CH₃.24. The compound of claim 23, wherein R^(6a) is substituted with one ormore —OR^(A6) groups, wherein R^(A6) is hydrogen or substituted orunsubstituted alkyl.
 25. The compound of claim 1, wherein R^(6a) is asubstituted or unsubstituted C₂₋₄ alkyl, substituted or unsubstitutedC₂₋₃ alkenyl, substituted or unsubstituted C₂₋₃ alkynyl, or substitutedor unsubstituted C₃ carbocyclyl, and R^(6b) is —CH₃. 26-27. (canceled)28. The compound of claim 1, wherein R¹ is C₁₋₃ alkyl, R^(6a) is anon-hydrogen group substituted with fluorine, and R^(6b) is —CH₃. 29.The compound of claim 1, wherein R¹ is C₁₋₃ alkyl, R^(6a) is anon-hydrogen group substituted with fluorine, and R^(6b) is hydrogen.30. The compound of claim 1, wherein R¹ is C₁₋₃ alkyl, R^(6a) is anon-hydrogen group selected from the group consisting of substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, andR^(6b) is —CH₃. 31-33. (canceled)
 34. The compound of claim 1, whereinR¹ is —CH₃ or —CH₂CH₃ and at least one of R^(5a) and R^(5b) is fluorineor R^(5a) and R^(5b) are both hydrogen.
 35. The compound of claim 1,wherein R¹ is —CH₃ or —CH₂CH₃ and R^(6a) is a non-hydrogen groupsubstituted with fluorine or one or more —OR^(A6) groups, wherein R^(A6)is hydrogen or substituted or unsubstituted alkyl. 36-37. (canceled) 38.The compound of claim 1 selected from the group consisting of:

and pharmaceutically acceptable salts thereof.
 39. A pharmaceuticalcomposition comprising a compound or pharmaceutically acceptable saltthereof of claim 1, and a pharmaceutically acceptable carrier.
 40. Amethod for treating or preventing a CNS-related condition comprisingadministering to a subject in need thereof an effective amount of acompound or pharmaceutically acceptable salt thereof, or pharmaceuticalcomposition thereof, of claim
 1. 41. (canceled)